Small molecules useful in the treatment of inflammatory disease

ABSTRACT

Compounds of the formula I  
                 
 
     which are useful for treating or preventing inflammatory and immune cell-mediated diseases. Exemplary are:

RELATED APPLICATIONS

[0001] This application is a division of nonprovisional application Ser.No. 10/195,973, filed on Jul. 16, 2002, which is a continuation ofnonprovisional application Ser. No. 09/604,312, filed on Jun. 27, 2000,now U.S. Pat. No. 6,492,408 B1, which claims benefit of priorprovisional application Serial No. 60/144,905, filed on Jul. 21, 1999and prior provisional application Serial No. 60/150,939, filed on Aug.26, 1999, all of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates generally to a series of novelsmall molecules, their synthesis and their use in the treatment ofinflammatory disease.

BACKGROUND OF THE INVENTION

[0003] Research spanning the last decade has helped to elucidate themolecular events attending cell-cell interactions in the body,especially those events involved in the movement and activation of cellsin the immune system. See generally, Springer, T. Nature, 1990, 346,425-434. Cell surface proteins, and especially the Cellular AdhesionMolecules (“CAMs”) and “Leukointegrins”, including LFA-1, MAC-1 andgp150.95 (referred to in WHO nomenclature as CD18/CD11a, CD18/CD11b, andCD18/CD11c, respectively) have correspondingly been the subject ofpharmaceutical research and development having as its goal theintervention in the processes of leukocyte extravasation to sites ofinjury and leukocyte movement to distinct targets. For example, it ispresently believed that prior to the leukocyte extravasation, which is amandatory component of the inflammatory response, activation ofintegrins constitutively expressed on leukocytes occurs and is followedby a tight ligand/receptor interaction between integrins (e.g., LFA-1)and one or several distinct intercellular adhesion molecules (ICAMs)designated ICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on bloodvessel endothelial cell surfaces and on other leukocytes. Theinteraction of the CAMs with the Leukointegrins is a vital step in thenormal functioning of the immune system. Immune processes such asantigen presentation, T-cell mediated cytotoxicity and leukocyteextravasation all require cellular adhesion mediated by ICAMsinteracting with the Leukointegrins. See generally Kishimoto, T. K.;Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.;Springer, T. Current Biology, 1994, 4, 506-532.

[0004] A group of individuals has been identified which lack theappropriate expression of Leukointegrins, a condition termed “LeukocyteAdhesion Deficiency” (Anderson, D. C.; et al., Fed. Proc. 1985, 44,2671-2677 and Anderson, D. C.; et al., J. Infect. Dis. 1985, 152,668-689). These individuals are unable to mount a normal inflammatoryand/or immune response(s) due to an inability of their cells to adhereto cellular substrates. These data show that immune reactions aremitigated when lymphocytes are unable to adhere in a normal fashion dueto the lack of functional adhesion molecules of the CD18 family. Byvirtue of the fact that LAD patients who lack CD18 cannot mount aninflammatory response, it is believed that antagonism of CD18, CD11/ICAMinteractions will also inhibit an inflammatory response.

[0005] It has been demonstrated that the antagonism of the interactionbetween the CAMs and the Leukointegrins can be realized by agentsdirected against either component. Specifically, blocking of the CAMs,such as for example ICAM-1, or the Leukointegrins, such as for exampleLFA-1, by antibodies directed against either or both of these moleculeseffectively inhibits inflammatory responses. In vitro models ofinflammation and immune response inhibited by antibodies to CAMs orLeukointegrins include antigen or mitogen-induced lymphocyteproliferation, homotypic aggregation of lymphocytes, T-cell mediatedcytolysis and antigen-specific induced tolerance. The relevance of thein vitro studies are supported by in vivo studies with antibodiesdirected against ICAM-1 or LFA-1. For example, antibodies directedagainst LFA-1 can prevent thyroid graft rejection and prolong heartallograft survival in mice (Gorski, A.; Immunology Today, 1994, 15,251-255). Of greater significance, antibodies directed against ICAM-1have shown efficacy in vivo as anti-inflammatory agents in humandiseases such as renal allograft rejection and rheumatoid arthritis(Rothlein, R. R.; Scharschmidt, L., in: Adhesion Molecules; Wegner, C.D., Ed.; 1994, 1-38, Cosimi, C. B.; et al., J. Immunol. 1990, 144,4604-4612 and Kavanaugh, A.; et al., Arthritis Rheum. 1994, 37,992-1004) and antibodies directed against LFA-1 have demonstratedimmunosuppressive effects in bone marrow transplantation and in theprevention of early rejection of renal allografts (Fischer, A.; et al.,Lancet, 1989, 2, 1058-1060 and Le Mauff, B.; et al., Transplantation,1991, 52, 291-295).

[0006] It has also been demonstrated that a recombinant soluble form ofICAM-1 can act as an inhibitor of the ICAM-1 interaction with LFA-1.Soluble ICAM-1 acts as a direct antagonist of CD18, CD11/ICAM-1interactions on cells and shows inhibitory activity in in vitro modelsof immune response such as the human mixed lymphocyte response,cytotoxic T cell responses and T cell proliferation from diabeticpatients in response to islet cells (Becker, J. C.; et al., J. Immunol.1993, 151, 7224 and Roep, B. O.; et al., Lancet, 1994, 343, 1590).

[0007] Thus, the prior art has demonstrated that large protein moleculeswhich antagonize the binding of the CAMs to the Leukointegrins havetherapeutic potential in mitigating inflammatory and immunologicalresponses often associated with the pathogenesis of many autoimmune orinflammatory diseases. However proteins have significant deficiencies astherapeutic agents, including the inability to be delivered orally andpotential immunoreactivity which limits the utility of theses moleculesfor chronic administration. Furthermore, protein-based therapeutics aregenerally expensive to produce.

[0008] Several small molecules have been described in the literaturewhich affect the interaction of CAMs and Leukointegrins. A naturalproduct isolated from the root of Trichilia rubra was found to beinhibitory in an in vitro cell binding assay (Musza, L. L.; et al.,Tetrahedron, 1994, 50, 11369-11378). One series of molecules (Boschelli,D. H.; et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H.; et al.,J. Med. Chem. 1995, 38, 4597-4614) was found to be orally active in areverse passive Arthus reaction, an induced model of inflammation thatis characterized by neutrophil accumulation (Chang, Y. H.; et al., Eur.J. Pharmacol. 1992, 69, 155-164). Another series of molecules was alsofound to be orally active in a delayed type hypersensitivity reaction inrats (Sanfilippo, P. J.; et al., J. Med. Chem. 1995, 38, 1057-1059). Allof these molecules appear to act nonspecifically, either by inhibitingthe transcription of ICAM-1 along with other proteins or actintracellularly to inhibit the activation of the Leukointegrins by anunknown mechanism. None of the molecules directly antagonize theinteraction of the CAMs with the Leukointegrins. Due to lack of potency,lack of selectivity and lack of a specific mechanism of action, thedescribed small molecules are not likely to be satisfactory fortherapeutic use.

[0009] It follows that small molecules having the similar ability aslarge protein molecules to directly and selectively antagonize thebinding of the CAMs to the Leukointegrins would make preferabletherapeutic agents. WO9839303 discloses a class of small moleculeinhibitors of the interaction of LFA-1 and ICAM-1. WO9911258 disclosesthat the fungal metabolite mevinolin and derivatives bind to LFA-1 anddisrupt the interaction of LFA-1 and ICAM-1. WO9949856 discloses a classof peptidomimetic inhibitors of ICAM binding to LFA-1 and Mac-1.

SUMMARY OF THE INVENTION

[0010] A first aspect of the invention comprises a method for treatingor preventing inflammatory and immune cell-mediated diseases by theadministration of certain novel small molecules. These compounds act byinhibiting the interaction of cellular adhesion molecules, specificallyby antagonizing the binding of human intercellular adhesion molecules(including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especiallyCD18/CD11a). A second aspect of the invention comprises novel smallmolecules having the above-noted therapeutic activities. A third aspectof the invention comprises methods for making these novel compounds. Afinal aspect of the invention comprises pharmaceutical compositionscomprising the above-mentioned compounds suitable for the prevention ortreatment of inflammatory and immune cell-mediated conditions.

DETAILED DESCRIPTION OF THE INVENTION

[0011] In its first and broadest aspect, the invention comprisescompounds of the formula I

[0012] wherein:

[0013] wherein:

[0014] A¹ is ═N— or ═C(H)—;

[0015] A² is ═N—, ═C(H)—, or ═C(R′)— wherein R′ is halogen, —CN,—Oalkyl, —CO₂alkyl or —SO₂alkyl, wherein the foregoing alkyl moietiesare of 1 to 3 carbon atoms;

[0016] D is ═N—, ═C(R¹)—, ═C(H)—, ═C(SO₂R¹)—, ═C(S(O)R¹)—, ═C(C(O)R¹)—,═C(C(O)H)—, ═C(SR^(1a))—, ═C(OR^(1a))— or ═C(NHR^(1a))—,

[0017]  wherein R¹ is selected from the class consisting of:

[0018] (A) —R¹⁰⁰, which is:

[0019] branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms,in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or morehydrogen atoms are optionally and independently replaced with:

[0020] (i) halogen,

[0021] (ii) oxo,

[0022] (iii) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:

[0023] (a) alkyl of 1 to 3 carbon atoms,

[0024] (b) —COOH,

[0025] (c) —SO₂OH,

[0026] (d) —PO(OH)₂,

[0027] (e) a group of the formula —COOR⁸, wherein R⁸ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0028] (f) a group of the formula —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁹ andR¹⁰ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

[0029] (g) a group of the formula —CONR¹¹R¹², wherein R¹¹ and R¹² areeach independently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹¹ and R¹² constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-,

[0030] (h) a group of the formula —OR¹³, wherein R¹³ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0031] (i) a group of the formula —SR¹⁴, wherein R¹⁴ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0032] (j) —CN, or

[0033] (k) an amidino group of the formula

[0034]  wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0035] (l) halogen,

[0036] (m) a group of the formula —NHCONHalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0037] (n) a group of the formula —NHCOOalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0038] (iv) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms,

[0039] (v) —CN,

[0040] (vi) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-,

[0041] (vii) a group of the formula —OR²¹, wherein R²¹ is a hydrogenatom, or a straight or branched alkyl or acyl group of 1 to 7 carbonatoms, wherein one or more hydrogen atoms of said alkyl or acyl groupare optionally replaced with a group independently selected from theclass consisting of —OH, —Oalkyl (wherein the alkyl moiety contains 1 to6 carbon atoms), —NH₂, —NHMe and —NMe₂,

[0042] (viii) a group of the formula —SR²², wherein R²² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one ormore hydrogen atoms of said alkyl or acyl group are optionally replacedwith a group independently selected from the class consisting of —OH,—Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMeand —NMe₂,

[0043] (ix) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently,

[0044] (a) a hydrogen atom,

[0045] (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂,

[0046] (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2,

[0047] (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,or

[0048] (e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1or 2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbonatoms,

[0049] (x) a quaternary group of the formula

[0050]  wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable counter ion,

[0051] (xi) a saturated, or partially unsaturated heterocyclic groupconsisting of 3 to 7 ring atoms selected from N, O, C and S, includingbut not limited to imidazolinyl, imidazolidinyl, pyrrolinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl,benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein saidheterocyclic group is optionally mono- or polysubstituted with oxo, and

[0052] (xii) a cycloalkyl group of 3 to 7 carbon atoms,

[0053] (B) branched or unbranched carboxylic acid groups of 3 to 6carbon atoms,

[0054] (C) branched or unbranched phosphonic acid groups of 2 to 6carbon atoms,

[0055] (D) branched or unbranched sulfonic acid groups of 2 to 6 carbonatoms,

[0056] (E) amidino groups of the formula

[0057]  wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring,

[0058] (F) guanidino groups of the formula

[0059]  wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ areeach, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms,and wherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring,

[0060] (G) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:

[0061] (i) alkyl of 1 to 3 carbon atoms,

[0062] (ii) —COOH,

[0063] (iii) —SO₂OH,

[0064] (iv) —PO(OH)₂,

[0065] (v) a group of the formula —COOR³⁶, wherein R³⁶ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0066] (vi) a group of the formula —NR³⁷R³⁸, wherein R³⁷ and R³⁸ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, orwherein R³⁷ and R³⁸ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

[0067] (vii) a group of the formula —CONR³⁹R⁴⁰, wherein R³⁹ and R⁴⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R³⁹ and R⁴⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-,

[0068] (viii) a group of the formula —OR⁴¹, wherein R⁴¹ is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0069] (ix) a group of the formula —SR⁴², wherein R⁴² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0070] (x) —CN, or

[0071] (xi) an amidino group of the formula

[0072]  wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ andR⁴⁵ may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0073] (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are eachindependently a hydrogen atom, phenyl which is optionally mono-orpolysubstituted with halogen, or R¹⁰⁰, wherein R¹⁰⁰ is as hereinbeforedefined,

[0074] (I) saturated or unsaturated heterocyclic groups consisting of 3to 7 ring atoms selected from N, O, C and S, or bicyclic heterocyclicgroups consisting of 8 to 11 atoms selected from N, O, C and S,including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl,benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein saidheterocyclic group is optionally mono- or poly-substituted with moietiesselected from the class consisting of:

[0075] (i) oxo,

[0076] (ii) —OR¹⁰¹, wherein R¹⁰¹ is:

[0077] (a) a hydrogen atom,

[0078] (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0079] (c) acyl of 1 to 7 carbons, wherein any hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0080] (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently ahydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-, or

[0081] (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,

[0082] (iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0083] (a) a hydrogen atom,

[0084] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms,

[0085] (c) benzoyl,

[0086] (d) benzyl or

[0087] (e) phenyl, wherein said phenyl ring is optionally mono- orpolysubstituted with —OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbonatoms,

[0088]  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —S—, S(O)—, SO₂—,—NH—, or —NMe-,

[0089] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0090] (v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl oralkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, whereinone or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkylgroup is optionally replaced with a moiety independently selected fromthe class consisting of:

[0091] (a) oxo,

[0092] (b) —OH,

[0093] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0094] (d) —OCOCH₃,

[0095] (e) —NH₂,

[0096] (f) —NHMe,

[0097] (g) —NMe₂,

[0098] (h) —CO₂H, and

[0099] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0100] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of:

[0101] (a) —OH,

[0102] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0103] (c) —NH₂,

[0104] (d) —NHMe,

[0105] (e) —NMe₂,

[0106] (f) —NHCOMe,

[0107] (g) oxo,

[0108] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0109] (i) —CN,

[0110] (j) the halogen atoms,

[0111] (k) heterocycles selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, and

[0112] (l) aryl or heteroaryl selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,

[0113] (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is:

[0114] (a) aryl or heteroaryl which is selected from the groupconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbonatoms),

[0115] (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbonatoms), or

[0116] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms),

[0117] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0118] (a) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6 carbonatoms),

[0119] (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl isoptionally substituted with one or more halogen, straight or branchedalkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of1 to 6 carbon atoms), or

[0120] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogenor alkyl of 1 to 6 carbon atoms),

[0121] (ix) —CHO,

[0122] (x) the halogen atoms, and

[0123] (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,

[0124] (J) the halogen atoms, and

[0125] (K) —CN, and

[0126] wherein R^(1a) is R¹⁰⁰;

[0127] X is an oxygen or sulfur atom;

[0128] R³ is:

[0129] (A) a hydrogen atom, or

[0130] (B) branched or unbranched alkyl of 1 to 3 carbon atoms orcycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl groupis optionally substituted with:

[0131] (i) a group of the formula —OR⁴⁸, wherein R⁴⁸ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms, or

[0132] (ii) a group of the formula —NR⁴⁹R⁵⁰, wherein R⁴⁹ and R⁵⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, oracyl of 1 to 2 carbon atoms;

[0133] R⁴ is a group of the formula —(CR⁵¹R⁵²)_(x)(CR⁵³R⁵⁴)_(y)R⁵⁵,wherein,

[0134] x is 0 or 1,

[0135] y is 0 or 1,

[0136] R⁵¹, R⁵² and R⁵³ are each, independently:

[0137] (A) a hydrogen atom,

[0138] (B) a group of the formula —OR⁵⁶, wherein R⁵⁶ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms, or

[0139] (C) branched or unbranched alkyl of 1 to 3 carbon atoms orcycloalkyl of 3 to 5 carbon atoms,

[0140] R⁵⁴ is:

[0141] (A) a group of the formula R⁵⁷, wherein R⁵⁷ is independentlyselected from the same class as is R¹, or

[0142] (B) a group of the formula —OR⁵⁸, wherein R⁵⁸ is independentlyselected from the same class as is R¹;

[0143] R⁵⁵ is:

[0144] aryl or heteroaryl which is selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,wherein one or more of the hydrogen atoms of said aryl or heteroarylgroup is optionally and independently replaced with:

[0145] (A) R⁵⁹, which is aryl or heteroaryl selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more of the hydrogen atomsof said aryl or heteroaryl group is optionally and independentlyreplaced with:

[0146] (i) branched or unbranched alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo,

[0147] (ii) a group of the formula —COOR⁶⁰, wherein R⁶⁰ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0148] (iii) a group of the formula —NR⁶¹R⁶², wherein R⁶¹ and R⁶² areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbonatoms, or wherein R⁶¹ and R⁶² constitute a saturated hydrocarbon bridgeof 3 to 5 carbon atoms which together with the nitrogen atom betweenthem form a heterocyclic ring,

[0149] (iv) a group of the formula —CONR⁶³R⁶⁴, wherein R⁶³ and R⁶⁴ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁶³ andR⁶⁴ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

[0150] (v) a group of the formula —OR⁶⁵, wherein R⁶⁵ is a hydrogen atom,or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

[0151] (vi) a group of the formula —SR⁶⁶, wherein R⁶⁶ is a hydrogenatom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

[0152] (vii) —CN,

[0153] (viii) nitro, or

[0154] (ix) halogen,

[0155] (B) methyl, which is optionally mono- or polysubstituted withfluorine atoms and additionally is optionally monosubstituted with R⁵⁹,

[0156] (C) branched or unbranched alkyl of 2 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo,

[0157] (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0158] (E) a group of the formula —NR⁶⁸R⁶⁹, wherein R⁶⁸ and R⁶⁹ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbonatoms, or wherein R⁶⁸ and R⁶⁹ constitute a saturated hydrocarbon bridgeof 3 to 5 carbon atoms which together with the nitrogen atom betweenthem form a heterocyclic ring, and wherein one of R⁶⁸ and R⁶⁹ mayadditionally be the group R⁵⁹,

[0159] (F) a group of the formula —CONR⁷⁰R⁷¹, wherein R⁷⁰ and R⁷¹ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁷⁰ andR⁷¹ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, and wherein one of R⁷⁰ and R⁷¹ may additionally be the group R⁵⁹,

[0160] (G) a group of the formula —COR⁷², wherein R⁷² is a hydrogenatom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3to 5 carbon atoms or R⁵⁹,

[0161] (H) a group of the formula —OR⁷³, wherein R⁷³ is a hydrogen atom,an alkyl fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁵⁹,

[0162] (I) a group of the formula —SR⁷⁴, wherein R⁷⁴ is a hydrogen atom,an alkyl fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁵⁹,

[0163] (J) —CN,

[0164] (K) nitro, or

[0165] (L) halogen;

[0166] R⁵ is Cl or trifluoromethyl;

[0167] Z is ═N— or ═C(R⁶)— wherein R⁶ is a hydrogen, fluorine, chlorine,bromine or iodine atom, methyl or trifluoromethyl; and,

[0168] R⁷ is a hydrogen, fluorine, chlorine, bromine or iodine atom,methyl, —CN, nitro or trifluoromethyl, with the condition that when Z is═N— or ═C(H)—, R⁷ is chlorine, trifluoromethyl, —CN or nitro;

[0169] and pharmaceutically acceptable salts thereof.

[0170] As the term is used herein, a “pharmaceutically acceptablecounter ion” is any counter ion generally regarded by those skilled inthe pharmaceutical art as being pharmaceutically acceptable. For adiscussion of what are pharmaceutically acceptable counter ions,reference may be had to Stephen M. Bergle, Lyle D. Bighley and Donald C.Monkhouse, “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences,66 (1977), 1-19. By way of non-limiting example, the chloride, bromide,acetate, and sulphate ions are pharmaceutically acceptable counter ions.

[0171] Preferred are compounds of the formula I wherein:

[0172] A¹ is ═N— or ═C(H)—;

[0173] A² is ═N—, ═C(H)—, or ═C(R′)— wherein R′ is halogen, —CN,—Oalkyl, —CO₂alkyl or —SO₂alkyl, wherein the foregoing alkyl moietiesare of 1 to 3 carbon atoms;

[0174] D is ═N—, ═C(R¹)—, ═C(H)—, ═C(SO₂R¹)—, ═C(S(O)R¹)—, ═C(C(O)R¹)—,═C(C(O)H)—, ═C(SR^(1a))—, ═C(OR^(1a))— or ═C(NHR^(1a))—,

[0175]  wherein R¹ is selected from the class consisting of:

[0176] (A) —R^(100a), which is:

[0177] branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms,in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or morehydrogen atoms are optionally and independently replaced with:

[0178] (i) halogen,

[0179] (ii) oxo,

[0180] (iii) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:

[0181] (a) alkyl of 1 to 3 carbon atoms,

[0182] (b) —COOH,

[0183] (c) —SO₂OH,

[0184] (d) —PO(OH)₂,

[0185] (e) a group of the formula —COOR⁸, wherein R⁸ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0186] (f) a group of the formula —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁹ andR¹⁰ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

[0187] (g) a group of the formula —CONR¹¹R¹², wherein R¹¹ and R¹² areeach independently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹¹ and R¹² constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-,

[0188] (h) a group of the formula —OR¹³, wherein R¹³ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0189] (i) a group of the formula —SR¹⁴, wherein R¹⁴ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0190] (j) —CN, or

[0191] (k) an amidino group of the formula

[0192]  wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0193] (l) halogen,

[0194] (m) a group of the formula —NHCONHalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0195] (n) a group of the formula —NHCOOalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0196] (iv) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms,

[0197] (v) —CN,

[0198] (vi) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-,

[0199] (vii) a group of the formula —OR²¹, wherein R²¹ is a hydrogenatom, or a straight or branched alkyl or acyl group of 1 to 7 carbonatoms, wherein one or more hydrogen atoms of said alkyl or acyl groupare optionally replaced with a group independently selected from theclass consisting of —OH, —Oalkyl (wherein the alkyl moiety contains 1 to6 carbon atoms), —NH₂, —NHMe and —NMe₂,

[0200] (viii) a group of the formula —SR²², wherein R²² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one ormore hydrogen atoms of said alkyl or acyl group are optionally replacedwith a group independently selected from the class consisting of —OH,—Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMeand —NMe₂,

[0201] (ix) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently,

[0202] (a) a hydrogen atom,

[0203] (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂,

[0204] (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2,

[0205] (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,or

[0206] (e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1or 2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbonatoms,

[0207] (x) a quaternary group of the formula

[0208]  wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is pharmaceuticallyacceptable counter ion,

[0209] (xi) a saturated, or partially unsaturated heterocyclic groupconsisting of 3 to 7 ring atoms selected from N, O, C and S, includingbut not limited to imidazolinyl, imidazolidinyl, pyrrolinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl,benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein saidheterocyclic group is optionally mono- or polysubstituted with oxo, and

[0210] (xii) a cycloalkyl group of 3 to 7 carbon atoms,

[0211] (B) branched or unbranched carboxylic acid groups of 3 to 6carbon atoms,

[0212] (C) branched or unbranched phosphonic acid groups of 2 to 6carbon atoms,

[0213] (D) branched or unbranched sulfonic acid groups of 2 to 6 carbonatoms,

[0214] (E) amidino groups of the formula

[0215]  wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring,

[0216] (F) guanidino groups of the formula

[0217]  wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ areeach, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms,and wherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring,

[0218] (G) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:

[0219] (i) alkyl of 1 to 3 carbon atoms,

[0220] (ii) —COOH,

[0221] (iii) —SO₂OH,

[0222] (iv) —PO(OH)₂,

[0223] (v) a group of the formula —COOR³⁶, wherein R³⁶ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0224] (vi) a group of the formula —NR³⁷R³⁸, wherein R³⁷ and R³⁸ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, orwherein R³⁷ and R³⁸ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

[0225] (vii) a group of the formula —CONR³⁹R⁴⁰, wherein R³⁹ and R⁴⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R³⁹ and R⁴⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-,

[0226] (viii) a group of the formula —OR⁴¹, wherein R⁴¹ is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0227] (ix) a group of the formula —SR⁴², wherein R⁴² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0228] (x) —CN, or

[0229] (xi) an amidino group of the formula

[0230]  wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ andR⁴⁵ may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0231] (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are eachindependently a hydrogen atom, phenyl which is optionally mono- orpolysubstituted with halogen, or R^(100a), wherein R^(100a) is ashereinbefore defined,

[0232] (I) saturated or unsaturated heterocyclic groups consisting of 3to 7 ring atoms selected from N, O, C and S, or bicyclic heterocyclicgroups consisting of 8 to 11 atoms selected from N, O, C and S,including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl,benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein saidheterocyclic group is optionally mono- or poly-substituted with moietiesindependently selected from the class consisting of:

[0233] (i) oxo,

[0234] (ii) —OR¹⁰¹, wherein R¹⁰¹ is:

[0235] (a) a hydrogen atom,

[0236] (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0237] (c) acyl of 1 to 7 carbons, wherein any hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0238] (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently ahydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-, or

[0239] (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,

[0240] (iii) —CONR¹⁰⁵R⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0241] (a) a hydrogen atom,

[0242] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms,

[0243] (c) benzoyl,

[0244] (d) benzyl or

[0245] (e) phenyl, wherein said phenyl ring is optionally mono- orpolysubstituted with —OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbonatoms,

[0246]  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —S—, S(O)—, SO₂—,—NH—, or —NMe-,

[0247] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0248] (v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl oralkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, whereinone or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkylgroup is optionally replaced with a moiety independently selected fromthe class consisting of:

[0249] (a) oxo,

[0250] (b) —OH,

[0251] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0252] (d) —OCOCH₃,

[0253] (e) —NH₂,

[0254] (f) —NHMe,

[0255] (g) —NMe₂,

[0256] (h) —CO₂H, and

[0257] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0258] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of:

[0259] (a) —OH,

[0260] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0261] (c) —NH₂,

[0262] (d) —NHMe,

[0263] (e) —NMe₂,

[0264] (f) —NHCOMe,

[0265] (g) oxo,

[0266] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0267] (i) —CN,

[0268] (j) the halogen atoms,

[0269] (k) heterocycles selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, and

[0270] (l) aryl or heteroaryl selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,

[0271] (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is:

[0272] (a) aryl or heteroaryl which is selected from the groupconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbonatoms),

[0273] (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbonatoms), or

[0274] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms),

[0275] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0276] (a) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6 carbonatoms),

[0277] (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl isoptionally substituted with one or more halogen, straight or branchedalkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of1 to 6 carbon atoms), or

[0278] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogenor alkyl of 1 to 6 carbon atoms),

[0279] (ix) —CHO,

[0280] (x) the halogen atoms, and

[0281] (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,

[0282] (J) the halogen atoms, and

[0283] (K) —CN and,

[0284] wherein R^(1a) is R^(100a);

[0285] X is an oxygen or sulfur atom;

[0286] R³ is:

[0287] (A) a hydrogen atom, or

[0288] (B) branched or unbranched alkyl of 1 to 3 carbon atoms orcycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl groupis optionally substituted with:

[0289] (i) a group of the formula —OR⁴⁸, wherein R⁴⁸ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms, or

[0290] (ii) a group of the formula —NR⁴⁹R⁵⁰, wherein R⁴⁹ and R⁵⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, oracyl of 1 to 2 carbon atoms;

[0291] R⁴ is a group of the formula —CH₂R⁵⁵, wherein,

[0292] R⁵⁵ is:

[0293] aryl or heteroaryl which is selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,wherein one or more of the hydrogen atoms of said aryl or heteroarylgroup is optionally and independently replaced with:

[0294] (A) R^(59a), which is aryl or heteroaryl selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more of the hydrogen atomsof said aryl or heteroaryl group is optionally and independentlyreplaced with:

[0295] (i) branched or unbranched alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo,

[0296] (ii) a group of the formula —COOR⁶⁰, wherein R⁶⁰ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0297] (iii) a group of the formula —NR⁶¹R⁶², wherein R⁶¹ and R⁶² areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbonatoms, or wherein R⁶¹ and R⁶² constitute a saturated hydrocarbon bridgeof 3 to 5 carbon atoms which together with the nitrogen atom betweenthem form a heterocyclic ring,

[0298] (iv) a group of the formula —CONR⁶³R⁶⁴, wherein R⁶³ and R⁶⁴ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁶³ andR⁶⁴ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

[0299] (v) a group of the formula —OR⁶⁵, wherein R⁶⁵ is a hydrogen atom,or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

[0300] (vi) a group of the formula —SR⁶⁶, wherein R⁶⁶ is a hydrogenatom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

[0301] (vii) —CN,

[0302] (viii) nitro, or

[0303] (ix) halogen,

[0304] (B) methyl, which is optionally mono- or polysubstituted withfluorine atoms and additionally is optionally monosubstituted withR^(59a),

[0305] (C) branched or unbranched alkyl of 2 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo,

[0306] (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0307] (E) a group of the formula —NR⁶⁸R⁶⁹, wherein R⁶⁸ and R⁶⁹ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbonatoms, or wherein R⁶⁸ and R⁶⁹ constitute a saturated hydrocarbon bridgeof 3 to 5 carbon atoms which together with the nitrogen atom betweenthem form a heterocyclic ring, and wherein one of R⁶⁸ and R⁶⁹ mayadditionally be the group R^(59a),

[0308] (F) a group of the formula —CONR⁷⁰R⁷¹, wherein R⁷⁰ and R⁷¹ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁷⁰ andR⁷¹ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, and wherein one of R⁷⁰ and R⁷¹ may additionally be the groupR^(59a),

[0309] (G) a group of the formula —COR⁷², wherein R⁷² is a hydrogenatom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3to 5 carbon atoms or R^(59a),

[0310] (H) a group of the formula —OR⁷³, wherein R⁷³ is a hydrogen atom,an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R^(59a),

[0311] (I) a group of the formula —SR⁷⁴, wherein R⁷⁴ is a hydrogen atom,an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R^(59a),

[0312] (J) —CN,

[0313] (K) nitro, or

[0314] (L) halogen;

[0315] R⁵ is Cl or trifluoromethyl;

[0316] Z is ═N— or ═C(R⁶)— wherein R⁶ is a hydrogen, fluorine, chlorine,bromine or iodine atom, methyl or trifluoromethyl; and,

[0317] R⁷ is a hydrogen, fluorine, chlorine, bromine or iodine atom,methyl, —CN, nitro or trifluoromethyl, with the condition that when Z is═N— or ═C(H)—, R⁷ is chlorine, trifluoromethyl, —CN or nitro;

[0318] and pharmaceutically acceptable salts thereof.

[0319] More preferred are compounds of the formula I wherein:

[0320] A¹ is ═N— or ═C(H)—;

[0321] A² is ═N—, or ═C(H)—;

[0322] D is ═N—, ═C(R¹)—, ═C(H)—, ═C(SO₂R¹)—, ═C(C(O)H)— or ═C(C(O)R¹)—,wherein R¹ is selected from the class consisting of:

[0323] (A) —R^(100b), which is:

[0324] branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms,in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or morehydrogen atoms are optionally and independently replaced with:

[0325] (i) oxo,

[0326] (ii) phenyl, wherein one hydrogen atom of said phenyl group isoptionally replaced with:

[0327] (a) alkyl of 1 to 3 carbon atoms,

[0328] (b) —COOH,

[0329] (c) —SO₂OH,

[0330] (d) —PO(OH)₂,

[0331] (e) a group of the formula —COOR⁸, wherein R⁸ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0332] (f) a group of the formula —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁹ andR¹⁰ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

[0333] (g) a group of the formula —CONR¹¹R¹², wherein R¹¹ and R¹² areeach independently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹¹ and R¹² constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0334] (h) a group of the formula —OR¹³, wherein R¹³ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0335] (i) a group of the formula —SR¹⁴, wherein R¹⁴ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0336] (j) —CN, or

[0337] (k) an amidino group of the formula

[0338]  wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0339] (l) a group of the formula —NHCONHalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0340] (m) a group of the formula —NHCOOalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0341] (iii) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms,

[0342] (iv) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0343] (v) a group of the formula —OR²¹, wherein R²¹ is a hydrogen atom,or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms,wherein one or more hydrogen atoms of said alkyl or acyl group areoptionally replaced with a group independently selected from the classconsisting of —OH, —Oalkyl (wherein the alkyl moiety contains 1 to 6carbon atoms), —NH₂, —NHMe and —NMe₂,

[0344] (vi) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently,

[0345] (a) a hydrogen atom,

[0346] (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂,

[0347] (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2,

[0348] (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,or

[0349] (e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1or 2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbonatoms,

[0350] (vii) a quaternary group of the formula

[0351]  wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable counter ion, or

[0352] (viii) a cycloalkyl group of 3 to 7 carbon atoms,

[0353] (B) branched or unbranched carboxylic acid groups of 3 to 6carbon atoms,

[0354] (C) branched or unbranched phosphonic acid groups of 2 to 6carbon atoms,

[0355] (D) branched or unbranched sulfonic acid groups of 2 to 6 carbonatoms,

[0356] (E) amidino groups of the formula

[0357]  wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring,

[0358] (F) guanidino groups of the formula

[0359]  wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ areeach, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms,and wherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring,

[0360] (G) phenyl, wherein one or more hydrogen atoms of said phenylgroup are optionally and independently replaced with:

[0361] (i) alkyl of 1 to 3 carbon atoms,

[0362] (ii) —COOH,

[0363] (iii) —SO₂OH,

[0364] (iv) —PO(OH)₂,

[0365] (v) a group of the formula —COOR³⁶, wherein R³⁶ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0366] (vi) a group of the formula —NR³⁷R³⁸, wherein R³⁷ and R³⁸ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, orwherein R³⁷ and R³⁸ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

[0367] (vii) a group of the formula —CONR³⁹R⁴⁰, wherein R³⁹ and R⁴⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R³⁹ and R⁴⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0368] (viii) a group of the formula —OR⁴¹, wherein R⁴¹ is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0369] (ix) a group of the formula —SR⁴², wherein R⁴² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0370] (x) —CN, or

[0371] (xi) an amidino group of the formula

[0372]  wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ andR⁴⁵ may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0373] (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are eachindependently a hydrogen atom, phenyl which is optionally mono-orpolysubstituted with halogen, or R^(100b), wherein R^(100b) is ashereinbefore defined,

[0374] (I) saturated or unsaturated heterocyclic groups selected fromthe class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl,benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein saidheterocyclic group is optionally mono- or poly-substituted with moietiesindependently selected from the class consisting of:

[0375] (i) oxo,

[0376] (ii) —OR¹⁰¹, wherein R¹⁰¹ is:

[0377] (a) a hydrogen atom,

[0378] (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0379] (c) acyl of 1 to 7 carbons, wherein any hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0380] (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently ahydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —NH—, or —NMe-, or

[0381] (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,

[0382] (iii) —CONR¹⁰⁵R⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0383] (a) a hydrogen atom,

[0384] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms,

[0385] (c) benzoyl,

[0386] (d) benzyl or

[0387] (e) phenyl, wherein said phenyl ring is optionally mono- orpolysubstituted with —OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbonatoms,

[0388]  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe-,

[0389] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0390] (v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl oralkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, whereinone or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkylgroup is optionally replaced with a moiety independently selected fromthe class consisting of:

[0391] (a) oxo,

[0392] (b) —OH,

[0393] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0394] (d) —OCOCH₃,

[0395] (e) —NH₂,

[0396] (f) —NHMe,

[0397] (g) —NMe₂,

[0398] (h) —CO₂H, and

[0399] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0400] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of:

[0401] (a) —OH,

[0402] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0403] (c) —NH₂,

[0404] (d) —NHMe,

[0405] (e) —NMe₂,

[0406] (f) —NHCOMe,

[0407] (g) oxo,

[0408] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0409] (i) —CN,

[0410] (j) the halogen atoms,

[0411] (k) heterocycles selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, and

[0412] (l) aryl or heteroaryl selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,

[0413] (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is:

[0414] (a) aryl or heteroaryl which is selected from the groupconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbonatoms),

[0415] (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbonatoms), or

[0416] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms),

[0417] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0418] (a) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6 carbonatoms),

[0419] (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl isoptionally substituted with one or more halogen, straight or branchedalkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of1 to 6 carbon atoms), or

[0420] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogenor alkyl of 1 to 6 carbon atoms),

[0421] (ix) —CHO,

[0422] (x) the halogen atoms, and

[0423] (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,

[0424] (J) the halogen atoms, and

[0425] (K) —CN;

[0426] X is an oxygen atom;

[0427] R³ is branched or unbranched alkyl of 1 to 3 carbon atoms;

[0428] R⁴ is a group of the formula —CH₂R⁵⁵, wherein,

[0429] R⁵⁵ is:

[0430] aryl or heteroaryl which is selected from the class consisting ofphenyl, pyridyl, and pyrimidinyl, wherein one or more of the hydrogenatoms of said aryl or heteroaryl group is optionally and independentlyreplaced with:

[0431] (A) R^(59b), which is aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, and thiazolyl, wherein one of the hydrogen atoms of said arylor heteroaryl group is optionally replaced with:

[0432] (i) branched or unbranched alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo,

[0433] (ii) —CN,

[0434] (iii) nitro, or

[0435] (iv) halogen,

[0436] (B) methyl, which is optionally trisubstituted with fluorineatoms or is optionally monosubstituted with R^(59b),

[0437] (C) branched or unbranched alkyl of 2 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally monosubstituted with halogen or oxo,

[0438] (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0439] (E) a group of the formula —COR⁷², wherein R⁷² is a hydrogenatom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3to 5 carbon atoms or R^(59b),

[0440] (F) a group of the formula —OR⁷³, wherein R⁷³ is a hydrogen atom,an alkyl fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R^(59b),

[0441] (G) —CN,

[0442] (H) nitro, or

[0443] (I) halogen;

[0444] R⁵ is Cl;

[0445] Z is ═C(H)—; and,

[0446] R⁷ is Cl;

[0447] and pharmaceutically acceptable salts thereof.

[0448] Even more preferred are compounds of the formula I, wherein:

[0449] A¹ is ═N—;

[0450] A² is ═C(H)—;

[0451] D is ═C(R¹)—, ═C(H)—, ═C(SO₂R¹)—, ═C(C(O)H)— or ═C(C(O)R¹)—,wherein R¹ is selected from the class consisting of:

[0452] (A) —R^(100c), which is:

[0453] branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms,in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or morehydrogen atoms are optionally and independently replaced with:

[0454] (i) oxo,

[0455] (ii) phenyl, wherein one hydrogen atom of said phenyl group isoptionally replaced with:

[0456] (a) alkyl of 1 to 3 carbon atoms,

[0457] (b) —COOH,

[0458] (c) —SO₂OH,

[0459] (d) —PO(OH)₂,

[0460] (e) a group of the formula —COOR⁸, wherein R⁸ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0461] (f) a group of the formula —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁹ andR¹⁰ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

[0462] (g) a group of the formula —CONR¹¹R¹², wherein R¹¹ and R¹² areeach independently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹¹ and R¹² constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0463] (h) a group of the formula —OR¹³, wherein R¹³ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0464] (i) a group of the formula —SR¹⁴, wherein R¹⁴ is a hydrogen atom,or an alkyl or acyl group of 1 to 7 carbon atoms,

[0465] (j) —CN, or

[0466] (k) an amidino group of the formula

[0467]  wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0468] (l) a group of the formula —NHCONHalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0469] (m) a group of the formula —NHCOOalkyl, wherein the alkyl moietycontains 1 to 3 carbon atoms,

[0470] (iii) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms,

[0471] (iv) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0472] (v) a group of the formula —OR²¹, wherein R²¹ is a hydrogen atom,or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms,wherein one or more hydrogen atoms of said alkyl or acyl group areoptionally replaced with a group independently selected from the classconsisting of —OH, —Oalkyl (wherein the alkyl moiety contains 1 to 6carbon atoms), —NH₂, —NHMe and —NMe₂,

[0473] (vi) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently,

[0474] (a) a hydrogen atom,

[0475] (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂,

[0476] (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2,

[0477] (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,or

[0478] (e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1or 2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbonatoms,

[0479] (vii) a quaternary group of the formula

[0480]  wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable counter ion, or

[0481] (viii) a cycloalkyl group of 3 to 7 carbon atoms,

[0482] (B) branched or unbranched carboxylic acid groups of 3 to 6carbon atoms,

[0483] (C) branched or unbranched phosphonic acid groups of 2 to 6carbon atoms,

[0484] (D) branched or unbranched sulfonic acid groups of 2 to 6 carbonatoms,

[0485] (E) amidino groups of the formula

[0486]  wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring,

[0487] (F) guanidino groups of the formula

[0488]  wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ areeach, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms,and wherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring,

[0489] (G) phenyl, wherein one or more hydrogen atoms of said phenylgroup are optionally and independently replaced with:

[0490] (i) alkyl of 1 to 3 carbon atoms,

[0491] (ii) —COOH,

[0492] (iii) —SO₂OH,

[0493] (iv) —PO(OH)₂,

[0494] (v) a group of the formula —COOR³⁶, wherein R³⁶ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0495] (vi) a group of the formula —NR³⁷R³⁸, wherein R³⁷ and R³⁸ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, orwherein R³⁷ and R³⁸ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

[0496] (vii) a group of the formula —CONR³⁹R⁴⁰, wherein R³⁹ and R⁴⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R³⁹ and R⁴⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0497] (viii) a group of the formula —OR⁴¹, wherein R⁴¹ is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0498] (ix) a group of the formula —SR⁴², wherein R⁴² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

[0499] (x) —CN, or

[0500] (xi) an amidino group of the formula

[0501]  wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogenatom or alkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ andR⁴⁵ may additionally constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom(s) between them forma heterocyclic ring,

[0502] (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are eachindependently a hydrogen atom, phenyl which is optionallymonosubstituted with halogen, or R^(100c), wherein R^(100c) is ashereinbefore defined,

[0503] (I) saturated or unsaturated heterocyclic groups selected fromthe class consisting of pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclicgroups are optionally mono- or poly-substituted with moietiesindependently selected from the class consisting of:

[0504] (i) oxo,

[0505] (ii) —OR¹⁰¹, wherein R¹⁰¹ is:

[0506] (a) a hydrogen atom,

[0507] (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0508] (c) acyl of 1 to 7 carbons, wherein any hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0509] (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently ahydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —NH—, or —NMe-, or

[0510] (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,

[0511] (iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0512] (a) a hydrogen atom,

[0513] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms,

[0514] (c) benzoyl,

[0515] (d) benzyl or

[0516] (e) phenyl, wherein said phenyl ring is optionally mono- orpolysubstituted with —OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbonatoms,

[0517]  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe-,

[0518] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0519] (v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl oralkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, whereinone or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkylgroup is optionally replaced with a moiety independently selected fromthe class consisting of:

[0520] (a) oxo,

[0521] (b) —OH,

[0522] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0523] (d) —OCOCH₃,

[0524] (e) —NH₂,

[0525] (f) —NHMe,

[0526] (g) —NMe₂,

[0527] (h) —CO₂H, and

[0528] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0529] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of:

[0530] (a) —OH,

[0531] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0532] (c) —NH₂,

[0533] (d) —NHMe,

[0534] (e) —NMe₂,

[0535] (f) —NHCOMe,

[0536] (g) oxo,

[0537] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0538] (i) —CN,

[0539] (j) the halogen atoms,

[0540] (k) heterocycles selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,and

[0541] (l) aryl or heteroaryl selected from the class consisting ofphenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,

[0542] (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is:

[0543] (a) aryl or heteroaryl which is selected from the groupconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl thiazolyl and pyrazolyl, wherein said aryl or heteroaryl moietyis optionally substituted with one or more moieties selected from theclass consisting of the halogen atoms, straight or branched alkyl of 1to 6 carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6carbon atoms),

[0544] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclic group is optionally substituted with one ormore moieties selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁸ (wherein R¹¹⁸is hydrogen or alkyl of 1 to 6 carbon atoms), or

[0545] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms),

[0546] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0547] (a) aryl or heteroaryl which is selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl and pyrazolyl, wherein said aryl or heteroarylmoiety is optionally substituted with one or more moieties selected fromthe class consisting of the halogen atoms, straight or branched alkyl of1 to 6 carbons, and —OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6carbon atoms),

[0548] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclyl is optionally substituted with one or morehalogen, straight or branched alkyl of 1 to 6 carbons, or —OR¹²¹(wherein R¹²¹ is hydrogen or alkyl of 1 to 6 carbon atoms), or

[0549] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogenor alkyl of 1 to 6 carbon atoms),

[0550] (ix) —CHO,

[0551] (x) the halogen atoms, and

[0552] (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and imidazolyl,

[0553] (J) the halogen atoms, and

[0554] (K) —CN;

[0555] X is an oxygen atom;

[0556] R³ is branched or unbranched alkyl of 1 to 3 carbon atoms;

[0557] R⁴ is a group of the formula —CH₂R⁵⁵, wherein,

[0558] R⁵⁵ is:

[0559] phenyl, which is optionally substituted at the 4-position with:

[0560] (A) R^(59c), which is aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl,wherein one of the hydrogen atoms of said aryl or heteroaryl group isoptionally replaced with:

[0561] (i) branched or unbranched alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo,

[0562] (ii) —CN,

[0563] (iii) nitro, or

[0564] (iv) halogen,

[0565] (B) methyl,

[0566] (C) branched or unbranched alkyl of 2 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally monosubstituted with halogen or oxo,

[0567] (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0568] (E) a group of the formula —COR⁷², wherein R⁷² is a hydrogenatom, straight or branched alkyl of 1 to 5 carbon atoms, or cycloalkylof 3 to 5 carbon atoms,

[0569] (F) a group of the formula —OR⁷³, wherein R⁷³ is a hydrogen atom,an alkyl, or fluoroalkyl or acyl group of 1 to 7 carbon atoms,

[0570] (G) —CN,

[0571] (H) nitro, or

[0572] (I) halogen;

[0573] R⁵ is Cl;

[0574] Z is ═C(H)—; and,

[0575] R⁷ is Cl;

[0576] and pharmaceutically acceptable salts thereof.

[0577] Further preferred are compounds of the formula I wherein:

[0578] A¹ is ═N—;

[0579] A² is ═C(H)—;

[0580] D is ═C(H)—, ═C(SO₂R¹)— or ═C(C(O)R¹)—, wherein R¹ is selectedfrom the class consisting of:

[0581] (A) —R^(100d), which is:

[0582] branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms,in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or morehydrogen atoms are optionally and independently replaced with:

[0583] (i) oxo,

[0584] (ii) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms,

[0585] (iii) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0586] (iv) a group of the formula —OR²¹, wherein R²¹ is a hydrogenatom, or a straight or branched alkyl or acyl group of 1 to 7 carbonatoms, wherein one or more hydrogen atoms of said alkyl or acyl groupare optionally replaced with a group independently selected from theclass consisting of —OH, —Oalkyl (wherein the alkyl moiety contains 1 to6 carbon atoms), —NH₂, —NHMe and —NMe₂,

[0587] (v) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently,

[0588] (a) a hydrogen atom,

[0589] (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂,

[0590] (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2,

[0591] (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,or

[0592] (e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1or 2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbonatoms,

[0593] (vi) a quaternary group of the formula

[0594]  wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable counter ion, or

[0595] (vii) a cycloalkyl group of 3 to 7 carbon atoms,

[0596] (B) branched or unbranched carboxylic acid groups of 3 to 6carbon atoms,

[0597] (C) branched or unbranched phosphonic acid groups of 2 to 6carbon atoms,

[0598] (D) branched or unbranched sulfonic acid groups of 2 to 6 carbonatoms,

[0599] (E) amidino groups of the formula

[0600]  wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring,

[0601] (F) guanidino groups of the formula

[0602]  wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ areeach, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms,and wherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring,

[0603] (G) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are eachindependently a hydrogen atom, phenyl which is optionallymonosubstituted with halogen, or R^(100d), wherein R^(100d) is ashereinbefore defined,

[0604] (H) saturated or unsaturated heterocyclic groups selected fromthe class consisting of pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclicgroups are optionally mono- or poly-substituted with moietiesindependently selected from the class consisting of:

[0605] (i) oxo,

[0606] (ii) —OR¹⁰¹, wherein R¹⁰¹ is:

[0607] (a) a hydrogen atom,

[0608] (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0609] (c) acyl of 1 to 7 carbons, wherein any hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0610] (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently ahydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —NH—, or —NMe-, or

[0611] (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,

[0612] (iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0613] (a) a hydrogen atom,

[0614] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms,

[0615] (c) benzoyl,

[0616] (d) benzyl or

[0617] (e) phenyl, wherein said phenyl ring is optionally mono- orpolysubstituted with —OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbonatoms,

[0618]  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe-,

[0619] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0620] (v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl oralkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, whereinone or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkylgroup is optionally replaced with a moiety independently selected fromthe class consisting of:

[0621] (a) oxo,

[0622] (b) —OH,

[0623] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0624] (d) —OCOCH₃,

[0625] (e) —NH₂,

[0626] (f) —NHMe,

[0627] (g) —NMe₂,

[0628] (h) —CO₂H, and

[0629] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0630] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of:

[0631] (a) —OH,

[0632] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0633] (c) —NH₂,

[0634] (d) —NHMe,

[0635] (e) —NMe₂,

[0636] (f) —NHCOMe,

[0637] (g) oxo,

[0638] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0639] (i) —CN,

[0640] (j) the halogen atoms,

[0641] (k) heterocycles selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,and

[0642] (l) aryl or heteroaryl selected from the class consisting ofphenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,

[0643] (vii) —SO₂R¹⁰⁸ wherein R¹⁰⁸ is:

[0644] (a) aryl or heteroaryl which is selected from the groupconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl thiazolyl and pyrazolyl, wherein said aryl or heteroaryl moietyis optionally substituted with one or more moieties selected from theclass consisting of the halogen atoms, straight or branched alkyl of 1to 6 carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6carbon atoms),

[0645] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclic group is optionally substituted with one ormore moieties selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁸ (wherein R¹¹⁸is hydrogen or alkyl of 1 to 6 carbon atoms), or

[0646] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms),

[0647] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0648] (a) aryl or heteroaryl which is selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl and pyrazolyl, wherein said aryl or heteroarylmoiety is optionally substituted with one or more moieties selected fromthe class consisting of the halogen atoms, straight or branched alkyl of1 to 6 carbons, and —OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6carbon atoms),

[0649] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclyl is optionally substituted with one or morehalogen, straight or branched alkyl of 1 to 6 carbons, or —OR¹²¹(wherein R¹²¹ is hydrogen or alkyl of 1 to 6 carbon atoms), or

[0650] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogenor alkyl of 1 to 6 carbon atoms),

[0651] (ix) —CHO,

[0652] (x) the halogen atoms, and

[0653] (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and imidazolyl, and

[0654] (I) the halogen atoms,

[0655] X is an oxygen atom;

[0656] R³ is branched or unbranched alkyl of 1 to 3 carbon atoms;

[0657] R⁴ is a group of the formula —CH₂R⁵⁵, wherein,

[0658] R⁵⁵ is:

[0659] phenyl, which is optionally substituted at the 4-position with:

[0660] (A) R^(59d), which is aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl,wherein one of the hydrogen atoms of said aryl or heteroaryl group isoptionally replaced with:

[0661] (i) branched or unbranched alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo,

[0662] (ii) —CN,

[0663] (iii) nitro, or

[0664] (iv) halogen,

[0665] (B) methyl,

[0666] (C) branched or unbranched alkyl of 2 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally monosubstituted with halogen or oxo,

[0667] (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,

[0668] (E) a group of the formula —COR⁷², wherein R⁷² is a hydrogenatom, straight or branched alkyl of 1 to 5 carbon atoms, or cycloalkylof 3 to 5 carbon atoms,

[0669] (F) a group of the formula —OR⁷³, wherein R⁷³ is a hydrogen atom,an alkyl, or fluoroalkyl or acyl group of 1 to 7 carbon atoms,

[0670] (G) —CN,

[0671] (H) nitro, or

[0672] (I) halogen;

[0673] R⁵ is Cl;

[0674] Z is ═C(H)—; and,

[0675] R⁷ is Cl;

[0676] and pharmaceutically acceptable salts thereof.

[0677] Especially preferred are compounds of the formula I wherein:

[0678] A¹ is ═N—;

[0679] A² is ═C(H)—;

[0680] D is ═C(SO₂R¹)— or ═C(C(O)R¹)—, wherein R¹ is selected from theclass consisting of:

[0681] (A) —R^(100e), which is:

[0682] branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms,in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or morehydrogen atoms are optionally and independently replaced with:

[0683] (i) oxo,

[0684] (ii) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms,

[0685] (iii) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0686] (iv) a group of the formula —OR²¹, wherein R²¹ is a hydrogenatom, or a straight or branched alkyl or acyl group of 1 to 7 carbonatoms, wherein one or more hydrogen atoms of said alkyl or acyl groupare optionally replaced with a group independently selected from theclass consisting of —OH, —Oalkyl (wherein the alkyl moiety contains 1 to6 carbon atoms), —NH₂, —NHMe and —NMe₂, or

[0687] (v) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently,

[0688] (a) a hydrogen atom,

[0689] (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂,

[0690] (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2,

[0691] (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,or

[0692] (e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1or 2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbonatoms,

[0693] (B) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are eachindependently a hydrogen atom, phenyl which is optionallymonosubstituted with halogen, or R^(100e), wherein R^(100e) is ashereinbefore defined, and

[0694] (C) saturated or unsaturated heterocyclic groups selected fromthe class consisting of pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclicgroups are optionally mono- or poly-substituted with moietiesindependently selected from the class consisting of:

[0695] (i) oxo,

[0696] (ii) —OR¹⁰¹, wherein R¹⁰¹ is:

[0697] (a) a hydrogen atom,

[0698] (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0699] (c) acyl of 1 to 7 carbons, wherein any hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0700] (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently ahydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —NH—, or —NMe-, or

[0701] (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,

[0702] (iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0703] (a) a hydrogen atom, or

[0704] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms,

[0705]  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe-,

[0706] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0707] (v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl oralkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, whereinone or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkylgroup is optionally replaced with a moiety independently selected fromthe class consisting of:

[0708] (a) oxo,

[0709] (b) —OH,

[0710] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0711] (d) —OCOCH₃,

[0712] (e) —NH₂,

[0713] (f) —NHMe,

[0714] (g) —NMe₂,

[0715] (h) —CO₂H, and

[0716] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0717] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of:

[0718] (a) —OH,

[0719] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0720] (c) —NH₂,

[0721] (d) —NHMe,

[0722] (e) —NMe₂,

[0723] (f) —NHCOMe,

[0724] (g) oxo,

[0725] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0726] (i) —CN,

[0727] (j) the halogen atoms,

[0728] (k) heterocycles selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,and

[0729] (l) aryl or heteroaryl selected from the class consisting ofphenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,

[0730] (vii) —SO₂R¹⁸, wherein R¹⁰⁸ is:

[0731] (a) phenyl, wherein said phenyl moiety is optionally substitutedwith one or more moieties selected from the class consisting of thehalogen atoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹⁷(wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbon atoms),

[0732] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclic group is optionally substituted with one ormore moieties selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁸ (wherein R¹¹⁸is hydrogen or alkyl of 1 to 6 carbon atoms), or

[0733] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms),

[0734] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0735] (a) phenyl, wherein said phenyl moiety is optionally substitutedwith one or more moieties selected from the class consisting of thehalogen atoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹²⁰(wherein R¹²⁰ is hydrogen or alkyl of 1 to 6 carbon atoms),

[0736] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclyl is optionally substituted with one or morehalogen, straight or branched alkyl of 1 to 6 carbons, or —OR¹²¹(wherein R¹²¹ is hydrogen or alkyl of 1 to 6 carbon atoms), or

[0737] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogenor alkyl of 1 to 6 carbon atoms), and

[0738] (ix) —CHO;

[0739] X is an oxygen atom;

[0740] R³ is branched or unbranched alkyl of 1 to 3 carbon atoms;

[0741] R⁴ is a group of the formula —CH₂R⁵⁵, wherein,

[0742] R⁵⁵ is:

[0743] phenyl, which is optionally substituted at the 4-position with:

[0744] (A) R^(59e), which is aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl,wherein one of the hydrogen atoms of said aryl or heteroaryl group isoptionally replaced with:

[0745] (i) methyl,

[0746] (ii) —CN,

[0747] (iii) nitro, or

[0748] (iv) halogen,

[0749] (B) methyl,

[0750] (C) —CN,

[0751] (D) nitro, or

[0752] (E) halogen;

[0753] R⁵ is Cl;

[0754] Z is ═C(H)—; and,

[0755] R⁷ is Cl;

[0756] and pharmaceutically acceptable salts thereof.

[0757] More especially preferred are compounds of the formula I wherein:

[0758] A¹ is ═N—;

[0759] A² is ═C(H)—;

[0760] D is ═C(SO₂R¹)— or ═C(C(O)R¹)—, wherein R¹ is selected from theclass consisting of:

[0761] (A) —R^(100e), which is:

[0762] branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkylof 3 to 6 carbon atoms, in which alkyl, or cycloalkyl group one to threehydrogen atoms are optionally and independently replaced with:

[0763] (i) oxo,

[0764] (ii) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms,

[0765] (iii) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0766] (iv) a group of the formula —OR²¹, wherein R²¹ is a hydrogenatom, or a straight or branched alkyl or acyl group of 1 to 7 carbonatoms, or

[0767] (v) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently,

[0768] (a) a hydrogen atom,

[0769] (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms,

[0770] (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2,

[0771] (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,or

[0772] (e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1or 2, and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbonatoms, and

[0773] (B) saturated heterocyclic groups selected from the classconsisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, wherein said heterocyclic groups are optionally mono-or di-substituted with moieties independently selected from the classconsisting of:

[0774] (i) oxo,

[0775] (ii) —OR¹⁰, wherein R¹⁰ is:

[0776] (a) a hydrogen atom,

[0777] (b) alkyl of 1 to 7 carbons, wherein one hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0778] (c) acyl of 1 to 7 carbons, wherein one hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0779] (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently ahydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —NH—, or —NMe-, or

[0780] (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,

[0781] (iii) —CONR¹⁰⁵R⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0782] (a) a hydrogen atom, or

[0783] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms, wherein said alkyl or cycloalkyl group is optionallymonosubstituted with —OH, —OR¹²³ (wherein R¹²³ is an alkyl moiety of 1to 6 carbon atoms), —NH₂, —NHMe, —NMe₂, pyrrolidinyl, piperidinyl,piperazinyl or morpholinyl, or, wherein R¹⁰⁵ and R¹⁰⁶ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0784] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0785] (v) straight or branched alkyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbons, wherein one to three hydrogen atoms ofsaid alkyl or cycloalkyl group is optionally replaced with a moietyindependently selected from the class consisting of:

[0786] (a) oxo,

[0787] (b) —OH,

[0788] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0789] (d) —OCOCH₃,

[0790] (e) —NH₂,

[0791] (f) —NHMe,

[0792] (g) —NMe₂,

[0793] (h) —CO₂H, and

[0794] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0795] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or two hydrogen atoms of said acyl group isoptionally replaced with a moiety selected from the class consisting of:

[0796] (a) —OH,

[0797] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0798] (c) —NH₂,

[0799] (d) —NHMe,

[0800] (e) —NMe₂,

[0801] (f) —NHCOMe,

[0802] (g) oxo,

[0803] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0804] (i) —CN,

[0805] (j) the halogen atoms,

[0806] (k) heterocycles selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,and

[0807] (l) aryl or heteroaryl selected from the class consisting ofphenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,

[0808] (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is:

[0809] (a) phenyl, wherein said phenyl moiety is optionally substitutedwith one moiety selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁷ (wherein R¹¹⁷is hydrogen or alkyl of 1 to 6 carbon atoms),

[0810] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclic group is optionally substituted with onemoiety selected from the class consisting of the halogen atoms, straightor branched alkyl of 1 to 6 carbons, and —OR¹¹⁸ (wherein R¹¹⁸ ishydrogen or alkyl of 1 to 6 carbon atoms), or

[0811] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one moiety selected from theclass consisting of the halogen atoms, straight or branched alkyl of 1to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogen or alkyl of 1 to 6carbon atoms),

[0812] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0813] (a) phenyl, wherein said phenyl moiety is optionally substitutedwith one moiety selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹²⁰ (wherein R¹²⁰is hydrogen or alkyl of 1 to 6 carbon atoms),

[0814] (b) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,wherein said heterocyclyl is optionally substituted with one halogen,straight or branched alkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ ishydrogen or alkyl of 1 to 6 carbon atoms), or

[0815] (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one moeity selected from theclass consisting of the halogen atoms, straight or branched alkyl of 1to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogen or alkyl of 1 to 6carbon atoms), and

[0816] (ix) —CHO;

[0817] X is an oxygen atom;

[0818] R³ is branched or unbranched alkyl of 1 to 3 carbon atoms;

[0819] R⁴ is a group of the formula —CH₂R⁵⁵, wherein,

[0820] R⁵⁵ is:

[0821] phenyl, which is optionally substituted at the 4-position with:

[0822] (A) R^(59e), which is aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl,wherein one of the hydrogen atoms of said aryl or heteroaryl group isoptionally replaced with:

[0823] (i) methyl,

[0824] (ii) —CN,

[0825] (iii) nitro, or

[0826] (iv) halogen,

[0827] (B) methyl,

[0828] (C) —CN,

[0829] (D) nitro, or

[0830] (E) halogen;

[0831] R⁵ is Cl;

[0832] Z is ═C(H)—; and,

[0833] R⁷ is Cl;

[0834] and pharmaceutically acceptable salts thereof.

[0835] Penultimately preferred are compounds of formula I wherein:

[0836] A¹ is ═N—;

[0837] A² is ═C(H)—;

[0838] D is ═C(SO₂R¹)—, wherein R¹ is selected from the class consistingof:

[0839] (A) methyl, and

[0840] (B) saturated heterocyclic groups selected from the classconsisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinylwherein said heterocyclic groups are optionally mono- or di-substitutedwith moieties independently selected from the class consisting of:

[0841] (i) oxo,

[0842] (ii) —OR¹⁰¹, wherein R¹⁰¹ is:

[0843] (a) a hydrogen atom,

[0844] (b) alkyl of 1 to 7 carbons, wherein one hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, or

[0845] (c) acyl of 1 to 7 carbons, wherein one hydrogen atom of saidacyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂,

[0846] (iii) —CONR¹⁰⁵R⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently:

[0847] (a) a hydrogen atom, or

[0848] (b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3to 7 atoms, wherein said alkyl or cycloalkyl group is optionallymonosubstituted with —OH, —OR¹²³ (wherein R¹²³ is an alkyl moiety of 1to 6 carbon atoms), —NH₂, —NHMe, —NMe₂, pyrrolidinyl, piperidinyl,piperazinyl or morpholinyl, or, wherein R¹⁰⁵ and R¹⁰⁶ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-,

[0849] (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight orbranched alkyl of 1 to 7 carbon atoms,

[0850] (v) straight or branched alkyl of 1 to 7 carbon atoms wherein oneor two hydrogen atoms of said alkyl group are optionally replaced withmoieties independently selected from the class consisting of:

[0851] (a) oxo,

[0852] (b) —OH,

[0853] (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms,

[0854] (d) —OCOCH₃,

[0855] (e) —NH₂,

[0856] (f) —NHMe,

[0857] (g) —NMe₂,

[0858] (h) —CO₂H, and

[0859] (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, orcycloalkyl of 3 to 7 carbons,

[0860] (vi) acyl of 1 to 7 carbon atoms, which may be straight, branchedor cyclic, and wherein one or two hydrogen atoms of said acyl group isoptionally replaced with a moiety selected from the class consisting of:

[0861] (a) —OH,

[0862] (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms,

[0863] (c) —NH₂,

[0864] (d) —NHMe,

[0865] (e) —NMe₂,

[0866] (f) —NHCOMe,

[0867] (g) oxo,

[0868] (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms,

[0869] (i) —CN,

[0870] (j) the halogen atoms,

[0871] (k) heterocycles selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,and

[0872] (l) aryl or heteroaryl selected from the class consisting ofphenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,

[0873] (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is:

[0874] (a) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein saidheterocyclic group is optionally substituted with one moiety selectedfrom the class consisting of straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbonatoms),

[0875] (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is:

[0876] (a) a heterocyclic group selected from the class consisting ofpyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein saidheterocyclyl is optionally substituted with one halogen, straight orbranched alkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen oralkyl of 1 to 6 carbon atoms), and

[0877] (ix) —CHO;

[0878] X is an oxygen atom;

[0879] R³ is methyl;

[0880] R⁴ is a group of the formula —CH₂R⁵⁵, wherein,

[0881] R⁵⁵ is:

[0882] phenyl, which is optionally substituted at the 4-position with:

[0883] (A) R^(59e), which is aryl or heteroaryl selected from the classconsisting of phenyl, pyridyl, and pyrimidinyl

[0884] (B) —CN,

[0885] (B) nitro, or

[0886] (C) halogen;

[0887] R⁵ is Cl;

[0888] Z is ═C(H)—; and,

[0889] R⁷ is Cl;

[0890] and pharmaceutically acceptable salts thereof.

[0891] It will be appreciated that the compounds of the formula I haveat least one chiral center. Ultimately preferred are those compounds offormula I with the absolute stereochemistry depicted below in formulaII.

[0892] Also preferred are the following specific compounds:

[0893] and their pharmaceutically acceptable salts.

[0894] Additionally it will be noted that certain compounds are usedulas intermediates in the synthesis of the above compounds of theinvention. In particular, compounds of the formula

[0895] wherein,

[0896] R¹ is selected from the class consisting of:

[0897] (A) hydrogen,

[0898] (B) the halogen atoms, and

[0899] (C) SO₂ ⁻M⁺, wherein M⁺ is

[0900] (i) Li⁺,

[0901] (ii) Na⁺,

[0902] (iii) K⁺, or

[0903] (iv) MgX⁺, wherein X is a halogen; and

[0904] R² is selected from the class consisting of:

[0905] (A) the halogen atoms,

[0906] (B) aryl, selected from the class of

[0907] (i) phenyl,

[0908] (ii) pyridyl, and

[0909] (iii) pyrimidyl, and

[0910] (C) CN.

[0911] Synthesis of the Compounds of the Invention

[0912] Compounds of the invention may be prepared by the general methodsdescribed below. Typically, reaction progress may be monitored by thinlayer chromatography (TLC) if desired. If desired, intermediates andproducts may be purified by chromatography on silica gel and/orrecrystallization, and characterized by one or more of the followingtechniques: NMR, mass spectroscopy and melting point. Starting materialsand reagents are either commercially available or may be prepared by oneskilled in the art using methods described in the chemical literature.

[0913] Intermediates used in the preparation of the compounds of formulaI may be prepared by the method described below and outlined in SchemeI.

[0914] An appropriate amino acid (III) is dissolved in aqueous base(such as, for example, NaOH, KOH, Na₂CO₃, NaHCO₃, K₂CO₃ or KHCO₃) andwarmed to between about 20 and 90° C. An appropriate isocyanate (IV) isadded to this mixture and the resulting solution is stirred until thereaction essentially reaches completion. Upon cooling, the mixture isacidified and the resulting ureidoacetic acid is isolated by filtrationor by extraction into organic solvent. Removal of solvent produces theintermediate ureidoacetic acid. In the manner reported by Sauli (U.S.Pat. No. 4,099,008), the intermediate ureidoacetic acid is cyclized byheating in the presence of a catalytic amount of acid (such as, forexample, sulfuric acid, methanesulfonic acid, benzenesulfonic acid orhydrochloric acid) in an organic or aqueous solvent, to produce thedesired hydantoin (V). Workup consists of collection of the hydantoin byfiltration and purification by, for example, silica gel chromatographyor recrystallization.

[0915] If the thiocarbonyl VII is desired, several reagents are known inthe literature which will convert carbonyls to thiocarbonyls. A typicalsequence involves heating the substrate with a reagent such as P₂S₃ in ahigh boiling solvent such as tetralin for between 1 and 48 h. Isolationof the product follows relatively standard conditions such as thedilution of the mixture into an organic solvent such as EtOAc andwashing this mixture with water and saturated aqueous NaCl followed bydrying and concentration. Purification is accomplished by silica gelchromatography or recrystallization, to afford VI.

[0916] Intermediate VI can be selectively hydrolyzed to the desiredmonothiocarbonyl compound depending on the choice of conditions. Ingeneral the thiocarbonyl at the 4-position of the ring is moresusceptible to nucleophilic conditions. It can be converted to the4-oxo-species (VII) by treatment with aqueous ethanolamine followed byacid hydrolysis. Purification is easily performed by silica gelchromatography or recrystallization.

[0917] Alternatively, the methyl or ethyl ester of III may be reactedwith an aryl thioisocyanate (IV: —NCS instead of —NCO) in a suitablesolvent, such as 1,4-dioxane, under an inert atmosphere at about 50-100°C. for about 1-24 h to provide VII.

[0918] If one uses the racemic III or ester of III, the product (V orVII) is racemic at the asymmetric carbon. By starting with a singleenantiomer of III or ester of III, one obtains the single enantiomer ofV or VII.

[0919] Compounds of formula I where A¹=N, A²=CH and D=CH may besynthesized as illustrated in Scheme II and described below.

[0920] Azide VIII is added to a solution of PPh₃ in a suitable solventsuch as toluene, under inert atmosphere and allowed to stir at ambienttemperature for about 12-24 h. The appropriate thiohydantoin VII is thenadded and the reaction heated under inert atmosphere, preferably in asealed tube at about 130-140° C. for about 1-4 days to provide IX afterconcentration and purification by silica gel chromatography. An acid,such as trifluoroacetic acid, is added to a solution of IX in a solventsuch as dichloroethane and heated under inert atmosphere at about50-100° C. for about 12-24 h to provide I after standard workup andpurification.

[0921] Analogs of I (A¹=N, A²=CH) where D is a carbon substituted withvarious groups, such as halogen, CN, CHO, an alkyl group, an alkyl oraryl sulfide, sulfoxide or sulfone, may be prepared as described belowand outlined in Scheme III.

[0922] In Scheme III, M is a metal atom such as Li or Mg, Hal is Cl, Bror I and E is a functional group transferable by an electrophilicreagent and can be, but is not restricted to, Cl, Br, I, CN, alkyl, CHO,SO₂M, SO₂R or CO₂R, where R is alkyl or aryl.

[0923] The desired N-halosuccinimide (about 1 mole equivalent) is addedin portions to a solution of I (A¹=N, A²=CH, D=CH), in a suitablesolvent such as methylene chloride at about −10° C. to ambienttemperature, preferably at about 0° C., and stirred for about 2 to 15 h.Following workup and purification, I (A¹=N, A²=CH, D=C—Cl, C—Br, C—I) isobtained.

[0924] The halogen substituted compound I (A¹=N, A²=CH, D=C—Cl, C—Br,C—I) may be transformed to an organometallic intermediate I (A¹=N,A²=CH, D=C-M, where M is a metal atom, such as Li or Mg) by treatmentwith an organometallic reagent, such as an alkyl or aryl lithium or aGrignard reagent. This organometallic intermediate may be reacted withan electrophile, such as an N-chloro-, bromo- or iodo-succinimide, tosylcyanide, an alkyl or aryl sulfonyl chloride, an alkyl or aryl disulfide,an alkyl- or arylthiosulfonate, an alkyl or aryl chloroformate, an alkylhalide, N,N-dimethylformamide or sulfur dioxide, to produce the anologof I (A¹=N, A²=CH) where D is a carbon substituted with various groups,such as Cl, Br, I, CN, an alkyl group, an alkyl or aryl sulfone, analkyl or aryl sulfide, CHO, or a sulfinate salt. The sulfides may befurther oxidized with a reagent, such as potassium peroxymonosulfate, orm-chlorobenzoic acid, to provide sulfoxides or sulfones. The sulfinatesalts may be further transformed to produce sulfones and sulfonamides asdescribed below.

[0925] More specifically, compounds I (A¹=N, A²=CH) with D=CN may beobtained by treating a solution of the corresponding halide, preferablyiodide I (A¹=N, A²=CH, D=C—I), in a solvent such as THF with an alkylmagnesium reagent, such as cyclopentyl magnesium bromide, at about −78to 0° C., preferably about −30 to −40° C., under an inert atmosphere,for about 1 to 5 h to generate an organomagnesium species I (A¹=N,A²=CH, D=C—Mg). Tosyl cyanide is then added and the reaction allowed togradually warm to ambient temperature and to proceed for about 1 to 24h. Following workup and purification, I (A¹=N, A²=CH, D=C—CN) isobtained.

[0926] Compounds I (A¹=N, A²=CH, D=C—SO₂R where R=alkyl or aryl) may beobtained by treating the organomagnesium species I (A¹=N, A²=CH, D=C—Mg)as generated above with an alkyl or aryl sulfonyl chloride.Alternatively, one may add an alkyl- or aryldisulfide, or an alkyl- orarylthiosulfonate (prepared by oxidizing the corresponding alkyl or aryldisulfide, for example with m-chloroperoxybenzoic acid in a suitablesolvent such as methylene chloride) and then heating the reaction atabout the reflux temperature of the solvent for about 1 to 3 h to obtainI (A¹=N, A²=CH, D=C—SR, where R=alkyl or aryl) after workup andpurification. The resulting product may be oxidized to the correspondingsulfoxide or sulfone with a suitable oxidizing agent such as potassiumperoxymonosulfate or m-chloroperoxybenzoic acid.

[0927] Compounds I (A¹=N, A²=CH) with D=C—CO₂R, where R is an alkyl oran aryl group, may be obtained by treating the organomagnesium speciesas generated above with an appropriate alkyl or aryl chloroformate, in asolvent such as THF, at about −20 to −78° C., preferably about −40° C.,under an inert atmosphere for about 15 min to 1 h before allowing thereaction to warm to room temperature over about 30 min to 1 h. Followingquenching, for example with aqueous sodium bicarbonate, workup andpurification, I (A¹=N, A²=CH, D=C—CO₂R) is obtained. Compounds I (A¹=N,A²=CH) with D=C—CHO may be obtained by treating a solution of thecorresponding halide, preferably iodide (I: A¹=N, A²=CH, D=C—I), in asolvent such as THF with an alkyl lithium, such as n-BuLi at about −50to −120° C., preferably about −100° C., under an inert atmosphere forabout 15 min to 1 h. N,N-Dimethylformamide is added and the reactiongradually allowed to warm to about 0° C. and stirred for about 1 h.Following quenching, for example with aqueous ammonium chloride, workupand purification, I (A¹=N, A²=CH, D=C—CHO) is obtained.

[0928] One may also synthesize certain compounds of the invention bytreating the organomagnesium intermediate as generated above with sulfurdioxide to generate an intermediate magnesium sulfinate salt. Thisintermediate may be treated with alkylating reagents, such as alkylhalides to produce additional compounds of the formula I (A¹=N, A²=CH)with D=C—SO₂R(R=alkyl). The intermediate magnesium sulfinate salt mayalso be treated with N-chlorosuccinimide to generate the sulfonylchloride I (A¹=N, A²=CH, D=C—SO₂Cl). The sulfonyl chloride can in turnbe treated with amines to produce desired sulfonamides I (A¹=N, A²=CH,D=C—SO₂NRR′ where R and R′=a hydrogen atom, an alkyl or aryl group, ortogether comprise part of a heterocyclic ring). Analogs of I (A¹=N,A²=CH) with D=C—SO₂NRR′ where R and R′ together comprise part of aheterocyclic ring and where R and/or R′ contains a second nitrogen, forexample piperazine, can be further substituted on the second nitrogen,for example with acyl, alkyl, aryl, carbamyl or sulfonyl as describedbelow and outlined in Scheme IV.

[0929] In Scheme IV, R″ is a functional group transferable by anelectrophilic reagent and can be, but is not restricted to, an alkylgroup, COR, CONRR′, CO₂R, or SO₂R, where R or R′ is alkyl or aryl.

[0930] The compound bearing the heteroatom can be treated with reagentssuch as an alkanoyl or aroyl chloride, alkanoyl or aroyl anhydride,alkyl halide, alkyl or aryl sulfonyl chloride or alkyl or arylisocyanate to produce compounds where I (A¹=N, A²=CH) and D is a carbonsubstituted with a sulfonamide which itself is further substituted withvarious groups such as alkyl or aryl amides, alkyl amines, alkyl or arylsulfonamides, and alkyl or aryl ureas.

[0931] More specifically, compounds I (A¹=N, A²=CH) and where D is acarbon substituted with a piperazinesulfonamide which itself is furtherN-acylated may be obtained by treating a solution of the correspondingpiperazinesulfonamide, in a solvent such as N,N-dimethylformamide withan appropriate carboxylic acid, in the presence of a coupling agent,such as polystyrene resin-bound carbodiimide, at about 20° C. for about2 to 24 h.

[0932] Following workup and purification, compounds I (A¹=N, A²=CH) andwhere D=is a carbon substituted with an acylated piperazinesulfonamideare obtained.

[0933] Alternatively, these compounds may be obtained by treating asolution of the corresponding piperazinesulfonamide, in a solvent suchas dichloromethane with an appropriate alkanoyl or aroyl chloride, inthe presence of a base, such as triethylamine, at about −20 to 20° C.,preferably about 0° C. for about 15 min to 2 h. Following quenching, forexample with aqueous sodium bicarbonate, workup and purification, thedesired acylated piperazinesulfonamides are obtained.

[0934] Compounds I (A¹=N, A²=CH) and where D is a carbon substitutedwith a piperazinesulfonamide which itself participates additionally inan urea linkage may be obtained by treating a solution of thecorresponding piperazinesulfonamide in a solvent such as dichloromethanewith an appropriate isocyanate, at about 0 to 40° C., preferably about20° C. for about 2 to 24 h. Following workup and purification, compoundsI (A¹=N, A²=CH) and where D=is a carbon substituted with an ureafunctionalized piperazinesulfonamide are obtained.

[0935] Alternatively, compounds I (A¹=N, A²=CH) and where D is a carbonsubstituted with a piperazinesulfonamide which itself is furtherN-sulfonylated may be obtained by treating a solution of thecorresponding piperazinesulfonamide, in a solvent such asdichloromethane with an appropriate sulfonyl chloride, in the presenceof a base, such as triethylamine, at about −20 to 20° C., preferablyabout 0° C. for about 15 min to 2 h. Following quenching, for examplewith aqueous sodium bicarbonate, workup and purification, compounds I(A¹=N, A²=CH) and where D=is a carbon substituted with a sulfonylatedpiperazinesulfonamide are obtained.

[0936] Functional group transformations well known in the art may beemployed to modify the substituents on D illustrated above to obtainadditional compounds of the invention.

[0937] Analogs of I (A¹=N, D=CH) where A² is a carbon substituted withvarious groups, such as halogen, CN, CHO, an alkyl group, an alkyl oraryl sulfide, sulfoxide or sulfone, may be prepared as described belowand outlined in Scheme V. In Scheme V, M is a metal atom, such as Li orMg, Hal is Cl, Br or I, and E is an functional group transferable by anelectrophilic reagent and can be, but is not restricted to, Cl, Br, I,CN, alkyl, CHO, SO₂M, SO₂R or CO₂R, where R is alkyl or aryl.

[0938] The desired N-halosuccinimide (about 2 mole equivalent relativeto I) is added in portions to a solution of I (A¹=N, A²=CH, D=CH), in asuitable solvent such as methylene chloride at about −10° C. to ambienttemperature, preferably at about 0° C., and stirred for about 2 to 15 h.Following workup and purification, I (A¹=N, A²=D=C-Cl, C—Br or C—I) isobtained.

[0939] The compound I (A¹=N, A²=D=C—Cl, C—Br or C—I) may be treated in asolvent such as THF with an alkyl magnesium bromide, such as cyclopentylmagnesium bromide, at about −78 to 0° C., preferably about −30 to −40°C., under an inert atmosphere, for about 1 to 5 h. An aqueous acid, suchas 1N hydrogen chloride or saturated NH₄Cl solution, is then added.Following workup and purification, I (A¹=N, A²=C—Cl, C—Br or C—I, andD=CH) is obtained.

[0940] The halogen substituted compound I (A¹=N, A²=C—Cl, C—Br or C—I,and D=CH) may be transformed to an organometallic intermediate I (A¹=N,A²=C-M, D=CH, where M is an metal atom, such as Li or Mg) by treatmentwith an organometallic reagent, such as an alkyl or aryl lithium ormagnesium reagent. This organometallic intermediate may be reacted withan electrophile, such as an N-chloro-, bromo- or iodo-succinimide, tosylcyanide, an alkyl halide, an alkyl or aryl sulfonyl chloride, an alkylor aryl disulfide, an alkyl- or arylthiosulfonate, an alkyl or arylchloroformate, N,N-dimethylformamide or sulfur dioxide, to produce theanalog of I (A¹=N, D=CH) where A² is a carbon substituted with variousgroups, such as Cl, Br, I, CN, an alkyl group, an alkyl or aryl sulfone,an alkyl or aryl sulfide, CHO, or a sulfinate salt. The sulfides may befurther oxidized with a reagent, such as potassium peroxymonosulfate, orm-chlorobenzoic acid, to sulfoxides or sulfones. The sulfinate salts mayalso be reacted with an alkylating reagent, such as an alkyl bromide oriodide to produce sulfones. Alternatively, the sulfinate salts may betransformed into the sulfonyl chlorides with a chlorinating reagent,such as NCS. The sulfonyl chlorides may be reacted with an amine toproduce sulfonamides I (A¹=N, A²=C—SO₂NR¹R², D=CH).

[0941] More specifically, compounds I (A¹=N, D=CH) with A²=C—CN, C—SO₂Ror CO₂R, where R is alkyl or aryl, C—CHO, C—SO₂Cl and C—SO₂NRR′ may beprepared from the corresponding halide or organomagnesium species asdescribed above (Scheme III) for D.

[0942] Functional group transformations well known in the art may beemployed to modify the substituents on A² illustrated above to obtainadditional compounds of the invention.

[0943] Functional group transformations also allow the derivatization ofR⁴. In particular, when R⁴ is a brominated or iodonated benzyl group,these halogens can often be replaced with aryl groups by techniquesknown in the art, for example by treating a solution of the halogenatedbenzyl group, with an organometallic reagent such as an aryl boronate,boronic acid or stannane, in a solvent such as a mixture of toluene andethanol, in the presence of a base, such as aqueous sodium carbonate,with a metal catalyst, such as Pd(PPh₃)₄, at about 75 to 110° C.,preferably about 85° C. for about 2 to 24 h. Following workup andpurification, I (R⁴=CH₂C₄H₆Ar) is obtained, where Ar can be, but is notlimited to, furyl, phenyl, pyridyl, pyrimidyl and thiophenyl.

[0944] Compounds of formula I with A¹=A²=D=N may be prepared asillustrated in Scheme VI and described below.

[0945] Intermediate VII is treated with an alkylating agent such asdiethyl sulfate, in a suitable solvent such as aqueous base and THF.After workup and purification, the intermediate is treated with asuitable oxidizing agent such as potassium peroxymonosulfate to givesulfoxide X. A solution of X is then treated with NaN₃ at ambienttemperature for about 12-24 h. Upon workup and purification, carboxylicacid XI is obtained. Intermediate XI is then reacted under standardpeptide coupling conditions, for example treatment with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and1-hydroxybenzotriazole (HOBT) and a base, such as diisopropylethylamine,in a suitable solvent such as DMF for about 5 to 24 h at ambienttemperature. Following workup and purification, I (A¹=A²=D=N) isobtained.

[0946] Compounds of formula I where A¹=N, A=N, and D=CH may be preparedas illustrated in Scheme VII and described below.

[0947] Intermediate X (Scheme VI) is treated with formic hydrazide in asuitable solvent such as DMSO, under an inert atmosphere at about 50 to100° C. for about 5 to 24 h to provide XII after workup andpurification. Intermediate XII is treated with a catalytic amount of anacid, such as p-toluenesulfonic acid in a suitable solvent, such astoluene. Molecular sieves or a trap to collect water formed in thereaction may be employed. The reaction is heated at reflux temperaturefor about 3 to 12 h. The desired compound of formula I (A¹=N, A²=N, andD=CH) is obtained following purification. Analogs of I (A¹=N, A²=N)where D=C substituted with various groups may be prepared as describedabove for analogs of I (A¹=N, A²=CH).

[0948] The invention is further described by the following syntheticexamples.

SYNTHETIC EXAMPLES Example 1

[0949]

[0950] A solution of amino-ester XIII and3,5-dichlorophenylisothiocyanate (1:1 molar ratio) in 1,4-dioxane washeated at 90° C. under N₂ for 10 h. The mixture was concentrated to givethe thiohydantoin derivative XIV. The product was characterized by ¹HNMR and mass spectroscopy.

[0951] To a solution of PPh₃ (9.0 mmol) in toluene (20 mL) under N₂ wasadded azide XV (9.0 mmol). After stirring at room temperature overnight,thiohydantoin XIV (4.5 mmol) was added. The mixture was sealed under N₂in a pressure tube and heated at 130-140° C. for 3-4 days, concentratedand purified by silica gel chromatography to gave the product XVI. Theproduct was characterized by ¹H NMR and mass spectroscopy.

[0952] To a solution of XVI in dichloroethane was added trifluoroaceticacid (TFA, 5-6 eq). The mixture was heated under N₂ at 90° C. overnight.The residue was taken up in EtOAc, washed with saturated NaHCO₃, dried(Na₂SO₄) and concentrated. The residue was purified by silica gelchromatography to give the title compound 1, m.p. 36-37.5° C. Theproduct was characterized by ¹H NMR and mass spectroscopy.

Example 2

[0953]

[0954] To a solution of compound 1 (1.82 g, 4.04 mmol), in CH₂Cl₂ (20mL), cooled to 0° C. was added in small portions N-iodosuccinimide (1.43g, 6.04 mmol). Pyridinium-p-toluenesulfonate (100 mg, 0.40 mmol) wasadded and the mixture was stirred at 0° C. for 3 h, during which,additional N-iodosuccinimide (400 mg, 1.68 mmol) was added to completethe reaction. The mixture was diluted with CH₂Cl₂, washed with 10%Na₂SO₃ solution, dried and concentrated. The residue was purified bysilica gel chromatography to give a mixture of the title compounds 2(1.86 g) and 2a (0.53 g). The products were characterized by ¹H NMR andmass spectroscopy.

[0955] Diiodide 2a may also be produced from 1 as the only product byusing more than 2 mole equivalents of N-iodosuccinimide in the sameprocedure as described above.

Example 3

[0956]

[0957] A solution of compound 2 (33 mg, 0.0572 mmol) in THF was treatedwith a 2.0 M solution of cyclopentylmagnesium bromide (57 μL, 0.114mmol) at −30° C. under nitrogen. The mixture was stirred at −30° C. for2 h before a solution of tosylcyanide (70 mg, 0.367 mmol) in THF (0.5mL) was added. The mixture was stirred at −30° C. for 1 h then at roomtemperature overnight. The reaction was quenched with a saturated NH₄Clsolution at 0° C. Extraction with EtOAc followed by silica gelchromatography gave compound 3 as a foam (9.5 mg, 35%). The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 4

[0958]

[0959] A solution of compound 2 (32 mg, 0.055 mmol) in THF was treatedwith n-BuLi (44 uL, 1.5 M, 0.067 mmol) at −100° C. under nitrogen. Themixture was stirred at −100° C. for 15 min before DMF (50 uL) was added.The mixture was stirred at −100° C. for 15 min then 0° C. for 1 h beforea saturated NH₄Cl solution (1 mL) was added. Extraction with EtOAcfollowed by silica gel chromatography gave compound 4 as an oil (3.0 mg,11%). The product was characterized by ¹H NMR and mass spectroscopy.

Example 5

[0960]

[0961] A solution of compound 2 (2.5 g, 4.33 mmol) in 25 mL of THF wastreated with cyclopentylmagnesium bromide (2.6 mL, 2 M, 5.2 mmol) at−40° C. under argon. The mixture was stirred at −40° C. for 40 min andthen SO₂ was bubbled in over 1 min. The mixture was stirred at −40° C.for 15 min then at room temperature for 1 h before being concentratedtwice under vacuum from dry THF to produce the solid magnesium salt 5.

Example 6

[0962]

[0963] The magnesium salt 5 (1.00 g, 1.62 mmol) was dissolved in 5 mL ofdry DMF and treated with MeI (0.5 mL, 8 mmol) at room temperature for1.5 h. It was then heated to between 40 and 50° C. for 1 h to completethe reaction. The reaction mixture was diluted with water to stop thereaction. Extraction with EtOAc followed by silica gel chromatographygave 6 (3.66 g, 66%). Mp=92-93° C. The product was characterized by ¹HNMR and mass spectroscopy.

Example 7

[0964]

[0965] For this example, the racemic iodide 2b was used as the startingmaterial. Compound 2b was prepared by the same procedure as compound 2,using racemic 1.

[0966] To a solution of anhydrous LiCl (10.0 mg, 0.236 mmol) and CuCN(10.5 mg, 0.117 mmol) in THF (0.2 mL), cooled at −20° C. was addedCH₃MgBr (1.4 M in THF, 0.21 mL, 0.294 mmol) under N₂. The solution wasstirred at −20° C. for 15 min. A solution of compound 2b (34 mg, 0.059mmol) in THF (0.5 mL) was added. The reaction mixture was stirred at−20° C. for 2 h and then at room temperature overnight before beingquenched with saturated aqueous NH₄Cl at 0° C. The mixture was extractedwith EtOAc, dried with Na₂SO₄ and concentrated. The residue was purifiedvia preparative thin layer chromatography (prep-TLC) to give 2 mg(yield: 6%) of 7. The product was characterized by ¹H NMR and massspectroscopy.

Example 8

[0967]

[0968] For this example, the racemic diiodide 2c was used as thestarting material. Compound 2c was prepared by the same procedure ascompound 2a, using racemic 1.

[0969] To a solution of compound 2c (766 mg, 1.09 mmol) in THF (10 mL)at −30° C. was added cyclopentylmagnesium bromide (2.0 M in ether, 1.36mL, 2.72 mmol) under nitrogen. The solution was stirred at −30° C. for1.5 h before a saturated aqueous NH₄Cl solution was added. The mixturewas warmed to room temperature and extracted with EtOAc. The organiclayer was dried with Na₂SO₄ and concentrated. The residue was purifiedby silica gel chromatography to give the iodide 8. The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 9 (9. BIRT0938XX)

[0970]

[0971] To a solution of the iodide 8 (113 mg, 0.196 mmol) in THF (1 mL)at −40° C. was added cyclopentylmagnesium bromide (2.0 M in ether, 0.293mL, 0.586 mmol) under nitrogen. The solution was stirred at −35° C. for90 min before methyl chloroformate (0.1 mL, 1.47 mmol) was added. Themixture was stirred at −35° C. for 30 min and then at room temperaturefor 1 h before a saturated aqueous solution of NH₄Cl was added. Themixture was extracted with EtOAc and the organic layer was dried withNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography to give the product 9 (16 mg). The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 10 (10. BIRT0937XX)

[0972]

[0973] A solution of the iodide 8 (32 mg, 0.055 mmol) in THF (0.8 mL)was treated cyclopentylmagnesium bromide (2.0 M in ether, 83 μL, 0.166mmol) at −30° C. under nitrogen. The mixture was stirred at −30° C. for1 h before a solution of tosylcyanide (53 mg, 0.28 mmol) in THF (0.2 mL)was added. The mixture was stirred at −30° C. for 10 min, then at roomtemperature for 1 h. The reaction was quenched with saturated NH₄Clsolution at 0° C. Extraction with EtOAc followed by silica gelchromatography gave compound 10 as a foam (10 mg). The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 11

[0974]

[0975] A solution of the iodide 8 (88 mg, 0.152 mmol) in THF (1 mL) wastreated with cyclopentylmagnesium bromide (2.0 M in ether, 230 μL, 0.46mmol) at −30° C. under nitrogen. The mixture was stirred at −30° C. for1 h before methanesulfonyl chloride (60 μL, 0.775 mmol) was added. Themixture was stirred at −30° C. for 1 h then at room temperature for 1 h.The reaction was quenched with saturated NaHCO₃ solution at 0° C.Extraction with EtOAc followed by silica gel chromatography gavecompound 11 (18 mg, 35%). The product was characterized by ¹H NMR andmass spectroscopy.

Example 12

[0976]

[0977] A solution of compound 6 (0.1 g, 0.19 mmol) in 2 mL of toluenewas treated with 5-trimethylstannylpyrimidine (0.07 g, 0.28 mmol) and Pd(PPh₃)₄ (22 mg, 0.02 mmol) and the mixture was heated to refluxovernight. Upon cooling, the solvent was removed by rotary evaporationand the residue was purified by preparative TLC. This produced 50.4 mgof compound 12. Mp=139-141° C. The product was characterized by ¹H NMRand mass spectroscopy.

Example 13

[0978]

[0979] A solution of compound 6 (90 mg, 0.17 mmol) in 2 mL of toluene, 1mL of EtOH and 0.8 mL of 2 M NaHCO₃ was treated with pyridine-3-boronicacid (37 mg, 0.22 mmol) and Pd(PPh₃)₄ (20 mg, 0,02 mmol). The mixturewas heated to reflux 1.5 h. Upon cooling, the solvent was removed byrotary evaporation and the residue was purified by silica gelchromatography. This produced 50.4 mg of compound 13. Mp=80-82° C. Theproduct was characterized by ¹H NMR and mass spectroscopy.

Example 14

[0980]

[0981] A solution of compound 2 (100 mg, 0.17 mmol) in 2.5 mL of THF wastreated with cyclopentylmagnesium bromide (0.14 mL, 2 M in ether, 0.28mmol) at −40° C. under argon. The mixture was stirred at −40° C. for 40min and then SO₂ was bubbled in over 1 min. The mixture was stirred at−40° C. for 15 min then at room temperature for 1 h and finally at 45°C. before being concentrated twice under vacuum from dry THF to producethe solid magnesium salt. The magnesium salt was treated with a mixtureof triethylamine (0.035 mL, 0.36 mmol) and N-chlorosuccinimide (71 mg,0.53 mmol). After 15 min, an excess of piperazine (119 mg, 1.38 mmol)was added and the reaction stirred at room temperature for 3 h. Themixture was then quenched by the addition of a solution of saturatedNH₄Cl and extracted into EtOAc. Upon concentration, the crude productwas purified using preparative TLC to yield compound 14 (26 mg) as anoil. The product was characterized by ¹H NMR and mass spectroscopy.

Example 15

[0982]

[0983] 2.00 mL of 1 N NaOH was added to a solution of 0.85 g (1.91 mmol)of XIV and 0.30 mL (0.35 g, 2.30 mmol) of diethyl sulfate in 8.5 mL ofTHF stirring in an ice-bath. After 10 min in the cold, the reaction waswarmed to room temperature and stirred 3.5 h. Aqueous ammonium chloridewas added and the reaction extracted with EtOAc, dried over MgSO₄, andconcentrated in vacuo to give an oil (0.98 g). Flash chromatography onsilica gel afforded 0.77 g (85%) of XVII as clear oil. The product wascharacterized by ¹H NMR and mass spectroscopy.

[0984] A solution of 0.69 g (1.13 mmol) of potassium peroxymonosulfatein 2.5 mL of 4×10⁻⁴ M EDTA was added to a stirred suspension of 0.76 g(1.61 mmol) of XVII and 0.68 g (8.05 mmol) of NaHCO₃ in 7.5 mL acetoneand 2.5 mL H₂O. After stirring 5 h, the reaction was diluted with EtOAcand washed with saturated aqueous Na₂SO₃ and brine. The combined aqueousphases were extracted with EtOAc and the combined organic phases weredried over MgSO₄ and concentrated in vacuo to give 0.82 g of XVIII as aclear oil. The product was characterized by ¹H NMR and massspectroscopy.

[0985] To this oil was added 0.48 g (8.05 mmol) of formic hydrazide and3.8 mL of dry DMSO and the reaction was heated at 60° C. under Ar for 10h. Water was added giving a white precipitate which was extracted intoEtOAc, washed with H₂O, dried over MgSO₄, and concentrated in vacuo to0.72 g of solid product. This was flash chromatographed on silica gel togive 0.31 g (41%) of XIX as a white solid.

[0986] A mixture of 0.15 g (0.319 mmol) of XIX and 15 mg ofp-toluenesulfonic acid and 0.30 g of 4 Å molecular sieves in 3 mL oftoluene was refluxed 5.5 h. The reaction was applied directly to asilica gel column and was purified via flash chromatography, to afford0.12 g (82%) of 15 as a yellow foamy resin. The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 16

[0987]

[0988] A solution of XVIII (Example 15) (130 mg, 0.266 mmol) in DMF (1mL) was treated with NaN₃ (140 mg, 2.15 mmol) at room temperature for 20h. The mixture was diluted with H₂O and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄) and concentrated. The residue waspurified by silica gel chromatography to give compound XX (80 mg, 64%).The product was characterized by ¹H NMR and mass spectroscopy.

[0989] To a solution of XX (28 mg, 0.060 mmol) in DMF (0.5 mL) was addedHOBT (16 mg, 0.118 mmol) and EDC (23 mg, 0.120 mmol). The mixture wasstirred at room temperature for 2 h before diisopropylethylamine (31 □L,0.18 mmol) was added. The mixture was stirred at room temperature for 10h, diluted with water, and extracted with methylene chloride. Theorganic layer was dried, concentrated and purified by silica gelchromatography to give 16 (15 mg, 56%). The product was characterized by¹H NMR and mass spectroscopy.

Example 17

[0990]

[0991] A mixture of 375 mg (0.709 mmol) of compound 6 and 70 mg (0.779mmol) copper (I) cyanide in 1.5 mL was stirred in dry DMF and heated for4 h at 160° C. under Ar. After cooling, water and EtOAc were added andthe reaction was filtered, the solids were washed with EtOAc, to afford90 mg of a green solid. The filtrate was extracted with EtOAc, washedwith water, dried, and concentrated under reduced pressure to 335 mg ofresin. The solids were suspended in 2 mL EtOAc and stirred overnightwith 16 μL SOCl₂. H₂O and EtOAc were added, the reaction was filteredand the filtrate extracted with EtOAc, washed with H₂Oand dried, andthen was concentrated under reduced pressure. The combined crudeproducts were purified via flash chromatography to afford 234 mg (69%)of compound 17 as a white resin, after drying under vacuum at 60° C. Theproduct was characterized by ¹H NMR and mass spectroscopy.

Example 18

[0992]

[0993] A mixture of 2.50 g (5.54 mmol) of compound 1 and 650 mg (7.20mmol) of copper (I) cyanide in 8 mL of dry DMF was stirred and heated 5h at 160° under Ar. After cooling, the mixture was poured into water andEtOAc was added and the reaction was filtered, and the solids werewashed with EtOAc, to afford 1.82 g of grey solid. The filtrate wasseparated and the organic phase washed with H₂O and concentrated underreduced pressure to give 1.35 g of an oil. The grey solids (1.4 g) wererefluxed with 0.27 mL SOCl₂ in 15 mL EtOAc for 0.5 h. After cooling, H₂Oand EtOAc were added, the reaction was filtered and the solids werewashed with EtOAc. The filtrate was extracted with EtOAc, the organiclayer was dried, and concentrated under reduced pressure. The crudeproducts were combined and purified via flash chromatography to 890 mg(36%) of unreacted 1, 960 mg (46%) of XXI, as well as 310 of mixedfractions.

[0994] N-iodosuccinimide (580 mg, 0.256 mmol) was added to a solution of960 mg (2.44 mmol) of XXI and 61 mg (0.244 mmol) of pyridiniump-toluenesulfonate in 10 mL methylene chloride at 0 C. The reaction wasallowed to warm to room temperature and was stirred overnight. Thereaction mixture was concentrated under reduced pressure, the residuediluted with EtOAc, washed with saturated aqueous Na₂S₂O₃, dried andconcentrated under reduced pressure. The 310 mg of mixed fraction weretreated similarly as described above. After isolation, the two residueswere combined and purified via flash chromatography to afford 1.08 g(64%) of compound XXII as a resin. The product was characterized by ¹HNMR and mass spectroscopy.

[0995] A solution of 2 M cyclopentylmagnesium bromide (1.24 mL, 2.48mmol) in Et₂O was added to a solution of 1.08 g (2.06 mmol) of XXII in20 mL dry Et₂O at −50° C., resulting in a white suspension. The reactionwas stirred for 15 min at −50 C and then SO₂ was bubbled in for 2 min.The reaction mixture was stirred for an additional 15 min at thattemperature, and then was stirred at room temp for 1 h. The reaction wasfiltered, the solids washed with Et₂O, and dried under vacuum for 0.5 hat room temperature to give 1.44 g of compound 18 as a beige solid.

Example 19

[0996]

[0997] To a stirred solution of 177 mg (1.33 mmol) N-chlorosuccinimidein 10 mL dry THF, was added 500 mg (0.709 mmol) of 18 giving a yellowsolution that was stirred 10 min. Piperazine (760 mg, 8.86 mmol) wasadded giving a pale suspension that was stirred 0.5 h. The reaction wasfiltered, the filtrate washed successively with water and 2N NaOH wasdried, and concentrated under reduced pressure. Purification of theresidue via flash chromatography afforded 225 mg (58%) of 19. Theproduct was characterized by ¹H NMR and mass spectroscopy.

Examples 20-22

[0998]

Example 20

[0999] To a stirred solution of 71 mg (0.532 mmol) N-chlorosuccinimidein 4 mL dry THF, was added 200 mg (0.283) of 18 giving a yellow solutionthat was stirred 10 min. Methyl isonipecotate (479 mL, 3.54 mmol) wasadded giving a beige suspension that was stirred 0.5 h. The reaction wasfiltered, the filtrate washed successively with water then 2N NaOH, wasdried and then was concentrated under reduced pressure. This residue waspurified via preparative TLC to give 87 mg (51%) of 20. The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 21

[1000] A stirred solution of 70 mg of 20 in 0.35 mL 30% HBr in aceticacid was stirred 3.5 h at 50° C. Water was added, the reaction wasfiltered and the solids were washed with H₂O. The solids were dissolvedin alcohol, precipitated with water and filtered, and then were driedunder vacuum at 50° C. to give 43 mg of a beige powder. The aqueousfiltrates were extracted with EtOAc to afford another 17 mg, to yield atotal of 60 mg (88%) of 21. The product was characterized by ¹H NMR andmass spectroscopy

Example 22

[1001] A solution of 13 mg (0.069 mmol) of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) and34 mg (0.058 mmol) of 21 in 1 mL CH₂Cl₂ was stirred for 0.5 h in at 0°C. Ammonia gas was bubbled in over 1 min and stirred for 15 min at 0° C.and then at room temperature for 7.5 h. An additional 13 mg of EDC wasadded to the reaction, which was then saturated with NH₃, sealed and thewas allowed to stir overnight. The reaction mixture was concentrated todryness under reduced pressure, and the residue was purified viapreparative TLC to afford 13 mg (38%) of 22 as a resin. The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 23

[1002]

[1003] A stirred solution of 27 mg (0.201 mmol) of N-chlorosuccinimideand 76 mg (0.107 mmol assuming 80% purity) of 18 in 2 mL dry THF wasstirred for 5 min at room temperature. N-Acetylpiperazine (86 mg, 0.67mmol) was added, and the resulting white suspension was stirred for 1 h.The reaction mixture was diluted with EtOAc, filtered and the filtratewas successively washed with 2N HCl, 2N NaOH and H₂O, was dried andconcentrated under reduced pressure. The residue was purified viapreparative TLC to give 33.5 mg (53%) of 23. The product wascharacterized by ¹H NMR and mass spectroscopy.

Example 24

[1004] This Example describes an alternate synthesis of intermediate XXIof Example 18

[1005] A solution of 15.1 mL (0.0151 mol) of 1 M lithiumbis(trimethylsilyl)amide in THF was added to 5.00 g (0.0126 mol) ofXXIII in 50 mL dry tetrahydrofuran at −10° C., and the orange solutionwas stirred for 0.5 h. A mixture of 2.96 g (0.151 mol)□-bromo-4-toluonitrile in 15 mL THF was added dropwise and the resultingsuspension was stirred for 5 h between −10 and ₀° C. Aqueous ammoniumchloride was added, and the aqueous layer was extracted with ether. Theorganic layer was dried and concentrated under reduced pressure. Theresidue was purified via flash chromatography and subsequentlyrecrystallized from CH₂Cl₂-pet ether to afford 5.04 g (78%) of a whitesolid. The product was characterized by ¹H NMR and mass spectroscopy.

[1006] A mixture of 5.00 g (9.67 mmol) of XXIV and 5.78 mL (14.6 mmol)of 40% benzyltrimethylammonium hydroxide in H₂O and 1.95 mL 10 N sodiumhydroxide in 25 mL of 1,4-dioxane was stirred at room temperature for 15h, then was heated at 40° C. for 1 h. The mixture was cooled to roomtemperature, then 16.3 mL (96.7 mmol) of 6 N HCl was added, and themixture was allowed to stir overnight. A solution of saturated aqueousNa₂CO₃ and the aqueous layer was extracted with EtOAc. The organic layerwas dried and concentrated under reduced pressure and the residue waspurified via flash chromatography to afford 2.78 g (82%) of XXV as anoil. The product was characterized by ¹H NMR and mass spectroscopy.

[1007] Thiophosgene (0.723 mL, 9.48 mmol) was added to a solution of2.75 g (7.90 mmol) XXV in 28 mL CH₂Cl₂ at 0° C., resulting in an orangesolution. Triethylamine (4.40 mL, 31.6 mmol) was added and the darksolution was allowed to warm to room temperature and was stirredovernight. The reaction was diluted with EtOAc, washed with saturatedaqueous NH₄Cl, re-extracted 2×EtOAc, then was dried and concentratedunder reduced pressure. The residue was purified via flashchromatography to afford 1.35 g recovered impure XXV as well as 1.08 gimpure XXVI. The recovered XXV was subjected to reaction conditionssimilar to that above, and after isolation and purification yielded anadditional 0.28 g of impure XXVI. The two samples were combined andpurified again via flash chromatography, to afford 0.92 g of purecompound XXVI. The product was characterized by ¹H NMR and massspectroscopy. Triphenylphosphine (1.18 g, 4.51 mmol) was addedportionwise to a solution of 580 mg (4.51 mmol) of XXVII in 10 mL ofxylenes and was stirred for 2 h at room temperature. A solution of 880mg (2.25 mmol) of XXVI in 2 mL of xylenes was added and the reaction washeated to reflux for 3 days and then was concentrated under reducedpressure. The residue was purified via flash chromatography to afford420 mg of impure XXVI, and 290 mg of impure XXVIII contaminated withtriphenylphosphine oxide The sample of XXVIII was treated with 0.49 mL(6.3 mmol) trifluoroacetic acid in 4 mL of 1,2-dichloroethane in apressure tube, purged with Ar, and heated at 110° C. overnight. Thereaction was then treated with saturated aqueous Na₂CO₃, extracted withether, then dried and concentrated under reduced pressure. The 420 mg ofimpure XXVI was treated under conditions similar to that describedabove. After isolation, both residues were combined and were purifiedvia flash chromatography to afford 120 mg (13%) of XXI as an oil. Theproduct was characterized by ¹H NMR and mass spectroscopy.

Example 25

[1008]

[1009] To a stirred solution of magnesium salt 5 (2.61 g, 4.22 mmol) inTHF (50 mL) was added N-chlorosuccinimide (0.79 g, 5.94 mmol). Theresulting mixture was stirred at room temperature for 1 h, then waspoured into brine and extracted with EtOAc. The combined extracts werewashed with brine, dried over MgSO₄ and filtered and the solvent wasremoved under reduced pressure. The residue was purified via silica gelchromatography to afford 1.77 g (76%) of 25 as a foam which wascharacterized via ¹H NMR and MS.

Example 26

[1010]

[1011] To a stirred solution of N-chlorosuccinimide (155 mg, 1.2 mmol)in THF (18 mL) at room temperature was added 5 (600 mg, 0.97 mmol). Theresulting yellow reaction mixture was stirred for 30 min, thenpiperazinone (214 mg, 2.1 mmol) was added in one portion, followed by afew drops of DMSO. The reaction mixture was stirred overnight, then wasdiluted with EtOAc, washed with brine, dried over MgSO₄ and filtered andthe solvent was removed under reduce pressure. The residue was purifiedvia silica gel chromatography to afford 240 mg (40%) of compound 26 as afoam which was characterized via ¹H NMR and MS.

Example 27

[1012]

[1013] To a stirred solution of 5 (308 mg; 0.50 mmol) in THF (12 mL) at−20° C. was added N-chlorosuccinimide (77.6 mg, 0.58 mmol). Theresulting mixture was stirred for 10 min, warned to 0° C. and thencooled back to −30° C. L-proline methyl ester hydrochloride (50 mg, 0.81mmol) was added followed by triethylamine (0.12 mL) and the reactionmixture was stirred for 2 h. The mixture was treated with saturatedaqueous ammonium chloride, and then was extracted with diethyl ether.The organic layer was dried over MgSO₄ and filtered and the residuepurified via preparative TLC to afford 127 mg (65%) of compound 27 as afoam which was characterized via ¹H NMR and MS.

Example 28

[1014]

[1015] To a stirred solution of N-chlorosuccinimide (325 mg, 2.4 mmol)in THF (10 mL) was added 5 (1.0 g, 1.6 mmol) in portions, at roomtemperature. The resulting yellow mixture was stirred for 5 min, then4-acetylpiperazine (830 mg, 6.5 mmol) was added. The reaction mixturewas allowed to stir for 1 h, then was treated with brine, and theaqueous layer was extracted with EtOAc. The organic layer was washedsuccessively with 1 M HCl, saturated aqueous sodium bicarbonate andbrine, then was dried over MgSO₄ and filtered and the solvent wasremoved under reduced pressure. The residue was purified via silica gelchromatography to afford 650 mg (63%) of compound 28 as a solid (m.p.153-155° C.) which was characterized via ¹H NMR and MS. Alternatively,compound 28 can also be prepared by the following method using compound14 (Example 14): to a stirred solution of 14 (200 mg, 0.33 mmol) in THF(20 mL) at 0° C. was added acetyl chloride (0.23 mL, 3.3 mmol) andtriethylamine (0.23 mL, 1.65 mmol). The reaction mixture was allowed towarm to room temperature over 1 h and was stirred an additional 1 h atthat temperature. The mixture was poured into saturated aqueous sodiumbicarbonate and the aqueous layer was extracted with EtOAc. The organiclayer was dried over MgSO₄ and filtered and the solvent was removedunder reduced pressure. The residue was purified via preparative TLC toafford 193 mg (90%) of compound 28 as a solid which exhibited identicalspectral characteristics with those of the title compound prepared viathe former method.

Example 29

[1016]

[1017] To a stirred solution of 25 (900 mg, 1.6 mmol) in dichloromethane(10 mL) was added a solution of 1-Boc-piperazine (670 mg, 3.6 mmol) indichloromethane dropwise at 0° C. The reaction mixture was warmed toroom temperature and allowed to stir for 2 h. The mixture was dilutedwith EtOAc, washed successively with 0.1 M HCl, water and brine, driedover MgSO₄ and filtered and the solvent was removed under reducedpressure. The residue was purified via silica gel chromatography toafford 931 mg (82%) of compound 29 as a foam which was characterized via¹H NMR and MS.

Example 30

[1018]

[1019] This example describes an alternate synthesis of compound 14(Example 14) To a stirred solution of 29 (3.43 g, 4.9 mmol) indichloromethane (30 mL) was added trifluoroacetic acid (5 mL, 65 mmol).The reaction mixture was allowed to stir at room temperature for 2 h,then was poured into 1 M NaOH and was extracted with dichloromethane.The organic layer was dried over MgSO₄ and filtered and the solvent wasremoved under reduced pressure. The residue was purified via silica gelchromatography to afford 2.20 g (75%) of 14 as a foam which wascharacterized via ¹H NMR and MS.

Example 31

[1020]

[1021] To a stirred solution of 14 (154 mg, 0.26 mmol) indichloromethane (1.5 mL) was added methyl isocyanate (0.024 mL, 0.39mmol). The reaction mixture was stirred for 0.5 h, then an additionalamount (0.024 mL, 0.39 mmol) of methyl isocyanate was added. Thereaction mixture was stirred for an additional 0.5 h, then the solventwas removed under reduced pressure to afford a quantitative yield of 31which was characterized via ¹H NMR and MS.

Example 32

[1022]

[1023] To a stirred solution of 3-hydroxypicolinic acid (138 mg, 0.99mmol) in N,N-dimethylformamide (10 mL) was added the PS-CDI resin (1.86g, 1.65 mmol). After 1 h, 14 (200 mg, 0.33 mmol) was added and thereaction mixture was allowed to stir overnight. The resin was filteredand then washed with dichloromethane and the combined organic layerswere poured into water. The aqueous layer was extracted withdichloromethane, then the organic layer was washed with brine, driedover MgSO₄ and filtered and the solvent was removed under reducedpressure. The residue was purified via preparative TLC to afford 89 mg(37%) of compound 32 as a foam which was characterized via ¹H NMR andMS.

Example 33

[1024]

[1025] To a stirred solution of morpholinoacetic acid (35 mg, 0.24 mmol)in N,N-dimethylformamide (8 mL) was added the PS-CDI resin (425 mg, 0.48mmol). After 1 h, 14 (50 mg, 0.08 mmol) was added and the reactionmixture was allowed to stir overnight. The resin was filtered and thenwashed with dichloromethane and the combined organic layers were pouredinto water. The aqueous layer was extracted with dichloromethane, thenthe organic layer was washed with brine, dried over MgSO₄ and filteredand the solvent was removed under reduced pressure. The residue waspurified via preparative TLC to afford 59 mg (98%) of compound 33 as afoam which was characterized via ¹H NMR and MS.

Example 34

[1026]

[1027] To a solution of 28 (29 mg, 0.045 mmol),3,5-difluorophenylboronic acid (0.026 mL, 50% wt/wt in THF/H₂O; 0.09mmol) and PdCl₂(dppf).CH₂Cl₂ (1.8 mg, 0.0022 mmol) in a mixture oftoluene (2 mL) and EtOH (1 mL) was added a solution of K₂CO₃ (25 mg,0.18 mmol) in water (0.5 mL). The reaction mixture was heated to refluxfor 4 h, then was diluted with toluene, and washed with brine, was driedover MgSO₄ and filtered and the solvent was removed under reducedpressure. The residue was purified via preparative TLC to afford 18.3 mg(60%) of compound 34 as a foam which was characterized via ¹H NMR andMS.

Example 35

[1028]

[1029] To a stirred solution of 28 (300 mg, 0.47 mmol) and5-(trimethylstannyl)pyrimidine (180 mg, 0.74 mmol) in toluene (10 mL)was added Pd(PPh₃)₄ (120 mg, 0.11 mmol) and the reaction mixture washeated to reflux for 15 h. Decolorizing charcoal was added to themixture, which was stirred and then filtered and the solvent was removedunder reduced pressure. The residue was purified via preparative TLC toafford 78 mg (26%) of compound 35 as a foam which was characterized via¹H NMR and MS.

Example 36

[1030]

[1031] To a stirred solution of 31 (168 mg, 0.26 mmol) andpyridine-3-boronic acid propanediol ester (59 mg, 0.36 mmol) in amixture of toluene (3 mL), ethanol (1.5 mL) and 2 M aqueous sodiumcarbonate (1.25 mL) was added Pd(PPh₃)₄ (59 mg, 0.05 mmol). The reactionmixture was heated to reflux for 1 h. The mixture was then filtered andthe organic layer was diluted with EtOAc, washed with water then driedover MgSO₄ and filtered and the solvent was removed under reducedpressure. The residue was purified via preparative TLC to afford 90 mg(32%) of compound 36 as a solid which was characterized via ¹H NMR andMS.

Example 37

[1032]

[1033] To a stirred solution of 6 (195 mg, 0.37 mmol) and3-thiopheneboronic acid (94 mg, 0.74 mmol) in a mixture of toluene (4.4mL), ethanol (2.2 mL) and 2 M aqueous sodium carbonate (0.55 mL) wasadded Pd(PPh₃)₄ (43 mg, 0.037 mmol). The reaction mixture was heated toreflux for 3 h, then was diluted with EtOAc and washed successively withwater and brine, dried over MgSO₄ and filtered and the solvent wasremoved under reduced pressure. The residue was purified via preparativeTLC to afford 123 mg (63%) of compound 37 as a foam which wascharacterized via ¹H NMR and MS.

Example 38

[1034]

[1035] To a stirred solution of 29 (860 mg, 1.23 mmol) andpyrimidine-5-boronic acid pinacol ester (506 mg, 2.46 mmol) in a mixtureof toluene (7 mL), ethanol (3.5 mL) and 2 M sodium carbonate (1.7 mL)was added Pd(PPh₃)₄ (142 mg, 0.12 mmol) and the reaction mixture washeated to reflux for 2 h. The mixture was diluted with EtOAc and washedsuccessively with water and brine, then was dried and filtered and thesolvent was removed under reduced pressure. The residue was purified viasilica gel chromatography to afford 790 mg (92%) of Boc-protected 38 asa foam. To a stirred solution of Boc-protected 38 (704 mg, 1.0 mmol) indichloromethane (15 mL) at room temperature was added trifluoroaceticacid (3 mL). The reaction mixture was stirred for 2 h, then was pouredinto 1 M sodium hydroxide and the aqueous layer was extracted withdichloromethane. The organic layer was washed with brine and dried overMgSO₄, was filtered and the solvent was removed under reduced pressure.The residue was purified via silica gel chromatography to afford 447 mg(64%) of compound 38 as a foam which was characterized via ¹H NMR andMS.

[1036] The following additional compounds of the invention were preparedby methods analogous to those described above. Each of the compoundsbelow was characterized by NMR and MS. Example No. Structure MeltingPoint (° C.) 39

>190 (decomp.) 40

resin 41

foam 42

foam 43

resin 44

resin 45

185-189 46

resin 47

resin 48

foam 49

not determined 50

not determined 51

75-82 52

not determined 53

not determined 54

79.1-80.9 55

foam 56

foam 57

not determined 58

not determined 59

195-197 60

not determined 61

not determined 62

not determined 63

not determined 64

foam 65

not determined 66

146-148 67

foam 68

not determined 69

foam 70

foam 71

not determined 72

not determined 73

not determined 74

145-147 75

not determined 76

not determined 77

hard oil 78

foam 79

83.5-87   80

not determined 81

158.0-159.3 82

foam 83

114.0-115.5 84

not determined 85

thick oil 86

65.6-67.0 87

oil 88

foam 89

163.7-165.2 90

not determined 91

not determined 92

90-95 93

not determined 94

not determined 95

foam 96

foam 97

oil 98

108-110 99

not determined 100

resin 101

not determined 102

foam 103

not determined 104

72.5-73.6 105

foam 106

oil 107

not determined 108

gummy foam 109

foam 110

foam 111

not determined 112

resin 113

resin 114

not determined 115

not determined 116

oil 117

foam 118

71.2-72.5 119

164.8-166.3 120

foam 121

125.5-127.8 122

not determined 123

201-203 124

101.8-103.6 125

resin 126

not determined 127

101-105 128

120.2-122.2 129

foam 130

foam 131

resin 132

oil 133

foam 134

foam 135

34.0-35.5 136

not determined 137

not determined 138

foam 139

166-169 140

not determined 141

resin 142

resin 143

foam 144

oil 145

not determined 146

foam 147

123.6-125.1 148

51.6-53.0 149

not determined 150

foam 151

not determined 152

amorphous 153

83.7-85.3 154

167-169 155

foam 156

170-174 157

not determined 158

foam 159

resin 160

foam 161

not determined 162

foam 163

not determined 164

not determined 165

not determined 166

112.6-113.6 167

foam 168

not determined 169

51.8-53.1 170

75 171

not determined 172

not determined 173

51-52 174

not determined 175

not determined 176

not determined 177

resin 178

not determined 179

not determined 180

resin 181

foam 182

not determined 183

80.5-85.5 184

not determined 185

foam 186

resin 187

resin 188

not determined 189

foam 190

foam 191

foam 192

not determined 193

not determined 194

not determined 195

66.5-68.1 196

150-160 197

not determined 198

not determined 199

resin 200

not determined 201

191-192 202

foam 203

foam 204

resin 205

not determined 206

oil 207

not determined 208

not determined 209

103-105 210

foam 211

not determined 212

not determined 213

not determined 214

187-189 215

film 216

not determined 217

foam 218

not determined 219

resin 220

79.1-81.0 221

100.9-102.2 222

not determined 223

not determined 224

foam 225

resin 226

not determined 227

170-172 228

114.9-116.0 229

not determined 230

not determined 231

foam 232

not determined 233

not determined 234

gummy solid 235

not determined 236

not determined 237

resin 238

foam 239

resin 240

resin 241

resin 242

resin 243

not determined 244

resin 245

100-102 246

67.2-68.5 247

not determined 248

foam 249

foam 250

not determined 251

foam 252

not determined 253

foam 254

  92-93.5 255

waxy solid 256

foam 257

foam 258

resin 259

170-171 260

not determined 261

thick oil 262

not determined 263

foam 264

111-114 265

176-178 266

resin 267

oil 268

not determined 269

not determined 270

not determined 271

not determined 272

not determined 273

 95-101 274

not determined 275

99.5-101  276

resin 277

foam 278

foam 279

110-115 280

oil 281

foam 282

not determined 283

not determined 284

waxy solid 285

foam 286

192-194 287

not determined 288

foam 289

not determined 290

not determined 291

not determined 292

not determined 293

not determined 294

foam 295

resin 296

not determined 297

not determined 298

71.2-72.3 299

not determined 300

96-99 301

resin 302

201-202 303

142-144 304

47.9-49.4 305

hard oil 306

foam 307

not determined 308

58-60 309

77.9-78.9 310

not determined 311

resin 312

resin 313

not determined 314

resin 315

not determined 316

resin 317

film 318

resin 319

74.1-76.0 320

not determined 321

foam 322

foam 323

foam 324

101.3-102.1 325

196-197 326

not determined 327

foam 328

not determined 329

132.3-133.7 330

not determined 331

oil 332

82.3-85.4 333

resin 334

resin 335

not determined 336

film 337

resin 338

139.2-140.0 339

126-127 340

foam 341

resin 342

not determined 343

resin 344

foam 345

88-90 346

not determined 347

not determined 348

72-78 349

90-95 350

foam 351

115.4-117.1 352

not determined 353

  90-92.5 354

oil 355

92-97 356

foam 357

film 358

not determined 359

foam 360

foam 361

foam 362

not determined 363

101-105 364

foam 365

resin 366

114.9-116.3 367

foam 368

88-92 369

not determined 370

not determined 371

not determined 372

125-126 373

109-114

[1037] Description of Biological Properties

[1038] The biological properties of representative compounds of theformula I were investigated by way of the experimental protocoldescribed below.

[1039] Assay to Determine Inhibition of LFA-1 Binding to ICAM-1

[1040] Purpose of Assay:

[1041] This assay protocol is designed to study the direct antagonism,by a test compound, of the interaction of the CAM, ICAM-1 with theLeukointegrin CD18/CD11a (LFA-1).

[1042] Description of Assay Protocol:

[1043] LFA-1 is immunopurified using the TS2/4 antibody from a 20 gpellet of human JY or SKW3 cells, utilizing a protocol previouslydescribed (Dustin, M. J.; et al., J. Immunol. 1992, 148, 2654-2660). TheLFA-1 is purified from SKW3 lysates by immunoaffinity chromatography onTS2/4 LFA-1 mAb Sepharose and eluted at pH 11.5 in the presence of 2 mMMgCl₂ and 1% octylglucoside. After collection and neutralization offractions from the TS2/4 column, samples are pooled and precleared withProtein G agarose.

[1044] A soluble form of ICAM-1 is constructed, expressed, purified andcharacterized as previously described (Marlin, S.; et al., Nature, 1990,344, 70-72 and see Arruda, A.; et al., Antimicrob. Agents Chemother.1992, 36, 1186-1192). Briefly, isoleucine 454 which is located at theputative boundary between domain 5 of the ectodomain and thetransmembrane domain, is changed to a stop codon using standardoligonucleotide-directed mutagenesis. This construction yields amolecule identical with the first 453 amino acids of membrane boundICAM-1. An expression vector is created with a hamster dihydrofolatereductase gene, a neomycin-resistance marker, and the coding region ofthe sICAM-1 construct described above, along with the promoter, splicesignals, and polyadenylation signal of the SV40 early region. Therecombinant plasmid is transfected into CHO DUX cells using standardcalcium phosphate methods. Cells are passaged in selective media (G418)and colonies secreting sICAM-1 are amplified using methotrexate. sICAM-1is purified from serum-free media using traditional non-affinitychromatographic techniques, including ion exchange and size exclusionchromatography.

[1045] LFA-1 binding to ICAM-1 is monitored by first incubating sICAM-1at 40 μg/mL in Dulbecco's phosphate buffered saline with calcium andmagnesium, additional 2 mM MgCl₂ and 0.1 mM PMSF (Diluting Buffer) in a96-well plate for 30 min at room temperature. Plates are then blocked bythe addition of 2% (w/v) bovine serum albumin in Diluting Buffer for 37°C. for 1 h. Blocking solution is removed from wells, and test compoundsare diluted and then added followed by the addition of approximately 25ng of immunoaffinity purified LFA-1. The LFA-1 is incubated in thepresence of test compound and ICAM-1 at 37° C. for 1 h. Wells are washed3 times with Diluting Buffer. The bound LFA-1 is detected by theaddition of a polyclonal antibody directed against a peptidecorresponding to the CD18 cytoplasmic tail in a 1:100 dilution withDiluting Buffer and 1% BSA and allowed to incubate for 45 min at 37° C.Wells are washed 3 times with Diluting Buffer and the bound polyclonalantibody is detected by the addition of a 1:4000 dilution of horseradish peroxidase conjugated to goat immunoglobulin directed againstrabbit immunoglobulin. This reagent is allowed to incubate for 20 min at37° C., wells are washed as above and the substrate for the horse radishperoxidase is added to each well to develop a quantitative colorimetricsignal proportional to the amount of LFA-1 bound to sICAM-1. SolubleICAM-1 (60 μg/mL) is used as a positive control for inhibition of theLFA-1/ICAM-1 interaction. The lack of the addition of LFA-1 to thebinding assay is used as a background control for all samples. Adose-response curve is obtained for all test compounds.

[1046] All compounds made in the above examples were tested in thisassay and each found to have a K_(d)<10 μM.

[1047] Description of Therapeutic Use

[1048] The novel small molecules of formula I provided by the inventioninhibit the ICAM-1/LFA-1 dependent homotypic aggregation of humanlymphocytes and human lymphocyte adherence to ICAM-1. These compoundshave therapeutic utility in the modulation of immune cellactivation/proliferation, e.g., as competitive inhibitors ofintercellular ligand/receptor binding reactions involving CAMs andLeukointegrins. To be more specific, the compounds of the invention maybe used to treat certain inflammatory conditions, including conditionsresulting from a response of the non-specific immune system in a mammal(e.g., adult respiratory distress syndrome, shock, oxygen toxicity,multiple organ injury syndrome secondary to septicemia, multiple organinjury syndrome secondary to trauma, reperfusion injury of tissue due tocardiopulmonary bypass, myocardial infarction or use with thrombolysisagents, acute glomerulonephritis, vasculitis, reactive arthritis,dermatosis with acute inflammatory components, stroke, thermal injury,hemodialysis, leukapheresis, ulcerative colitis, necrotizingenterocolitis and granulocyte transfusion associated syndrome) andconditions resulting from a response of the specific immune system in amammal (e.g., psoriasis, organ/tissue transplant rejection, graft vs.host reactions and autoimmune diseases including Raynaud's syndrome,autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoidarthritis, insulin-dependent diabetes mellitus, uveitis, inflammatorybowel disease including Crohn's disease and ulcerative colitis, andsystemic lupus erythematosus). The compounds of the invention may alsobe used in treating asthma or as an adjunct to minimize toxicity withcytokine therapy in the treatment of cancers. In general these compoundsmay be employed in the treatment of those diseases currently treatablethrough steroid therapy.

[1049] Thus, another aspect of the invention is the provision of amethod for the treatment or prophylaxis of the above-describedconditions through the adminstration of therapeutic or prophylacticamounts of one or more compounds of the formula I.

[1050] In accordance with the method provided by the invention, thenovel compounds of formula I may be administered for either aprophylactic or therapeutic purpose either alone or with otherimmunosuppressive or antiinflammatory agents. When providedprophylactically, the immunosuppressive compound(s) are provided inadvance of any inflammatory response or symptom (for example, prior to,at, or shortly after the time of an organ or tissue transplant but inadvance of any symptoms of organ rejection). The prophylacticadministration of a compound of the formula I serves to prevent orattenuate any subsequent inflammatory response (such as, for example,rejection of a transplanted organ or tissue, etc.). The therapeuticadministration of a compound of the formula I serves to attenuate anyactual inflammation (such as, for example, the rejection of atransplanted organ or tissue). Thus, in accordance with the invention, acompound of the formula I can be administered either prior to the onsetof inflammation (so as to suppress an anticipated inflammation) or afterthe initiation of inflammation.

[1051] The novel compounds of the formula I may, in accordance with theinvention, be administered in single or divided doses by the oral,parenteral or topical routes. A suitable oral dosage for a compound offormula I would be in the range of about 0.1 mg to 10 g per day. Inparenteral formulations, a suitable dosage unit may contain from 0.1 to250 mg of said compounds, whereas for topical administration,formulations containing 0.01 to 1% active ingredient are preferred. Itshould be understood, however, that the dosage administration frompatient to patient will vary and the dosage for any particular patientwill depend upon the clinician's judgement, who will use as criteria forfixing a proper dosage the size and condition of the patient as well asthe patient's response to the drug.

[1052] When the compounds of the present invention are to beadministered by the oral route, they may be administered as medicamentsin the form of pharmaceutical preparations which contain them inassociation with a compatible pharmaceutical carrier material. Suchcarrier material can be an inert organic or inorganic carrier materialsuitable for oral administration. Examples of such carrier materials arewater, gelatin, talc, starch, magnesium stearate, gum arabic, vegetableoils, polyalkylene-glycols, petroleum jelly and the like.

[1053] The pharmaceutical preparations can be prepared in a conventionalmanner and finished dosage forms can be solid dosage forms, for example,tablets, dragees, capsules, and the like, or liquid dosage forms, forexample solutions, suspensions, emulsions and the like. Thepharmaceutical preparations may be subjected to conventionalpharmaceutical operations such as sterilization. Further, thepharmaceutical preparations may contain conventional adjuvants such aspreservatives, stabilizers, emulsifiers, flavor-improvers, wettingagents, buffers, salts for varying the osmotic pressure and the like.Solid carrier material which can be used include, for example, starch,lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc,silica, dibasic calcium phosphate, and high molecular weight polymers(such as polyethylene glycol).

[1054] For parenteral use, a compound of formula I can be administeredin an aqueous or non-aqueous solution, suspension or emulsion in apharmaceutically acceptable oil or a mixture of liquids, which maycontain bacteriostatic agents, antioxidants, preservatives, buffers orother solutes to render the solution isotonic with the blood, thickeningagents, suspending agents or other pharmaceutically acceptableadditives. Additives of this type include, for example, tartrate,citrate and acetate buffers, ethanol, propylene glycol, polyethyleneglycol, complex formers (such as EDTA), antioxidants (such as sodiumbisulfite, sodium metabisulfite, and ascorbic acid), high molecularweight polymers (such as liquid polyethylene oxides) for viscosityregulation and polyethylene derivatives of sorbitol anhydrides.Preservatives may also be added if necessary, such as benzoic acid,methyl or propyl paraben, benzalkonium chloride and other quaternaryammonium compounds.

[1055] The compounds of this invention may also be administered assolutions for nasal application and may contain in addition to thecompounds of this invention suitable buffers, tonicity adjusters,microbial preservatives, antioxidants and viscosity-increasing agents inan aqueous vehicle. Examples of agents used to increase viscosity arepolyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone,polysorbates or glycerin. Microbial preservatives added may includebenzalkonium chloride, thimerosal, chloro-butanol or phenylethylalcohol.

[1056] Additionally, the compounds provided by the invention can beadministered topically or by suppository.

[1057] Formulations

[1058] Compounds of the formula I can be formulated for therapeuticadministration in a number of ways. Descriptions of several exemplaryformulations are given below.

Example A

[1059] Capsules or Tablets Example A-1 Example A-2 Ingredients QuantityIngredients Quantity Compound of for- 250 mg Compound of formula I 50 mgmula I Starch 160 mg Dicalcium Phosphate 160 mg  Microcrys. Cellulose 90 mg Microcrys. Cellulose 90 mg Sodium Starch Gly-  10 mg Stearic acid 5 mg colate Magnesium Stearate  2 mg Sodium Starch Glycolate 10 mgFumed colloidal silica  1 mg Fumed colloidal silica  1 mg

[1060] The compound of formula I is blended into a powder mixture withthe premixed excipient materials as identified above with the exceptionof the lubricant. The lubricant is then blended in and the resultingblend compressed into tablets or filled into hard gelatin capsules.

Example B

[1061] Parenteral Solutions Ingredients Quantity Compound of formula I500 mg PEG 400 40% by volume Ethyl Alcohol 5% by volume Saline 55% byvolume

[1062] The excipient materials are mixed and then added to one of thecompounds of formula I in such volume as is necessary for dissolution.Mixing is continued until the solution is clear. The solution thenfiltered into the appropriate vials or ampoules and sterilized byautoclaving.

Example C

[1063] Suspension Ingredients Quantity Compound of formula I 100 mgCitric acid 1.92 g Benzalkonium chloride 0.025% by weight EDTA 0.1% byweight Polyvinylalcohol 10% by weight Water q.s. to 100 mL

[1064] The excipient materials are mixed with the water and thereafterone of the compounds of formula I is added and mixing is continued untilthe suspension is homogeneous. The suspension is then transferred intothe appropriate vials or ampoules.

Example D

[1065] Topical Formulation Ingredients Quantity Compound of formula I 5%by weight Tefose 63 13% by weight  Labrafil M 1944 CS 3% by weightParaffin Oil 8% by weight Methylparaben (MP) 0.15% by weight  Propylparaben (PP) 0.05% by weight   Deionized water q.s. to 100

[1066] The proper amounts of Tefose 63, Labrafil M 1944 CS, Paraffin oiland water are mixed and heated at 75° C. until all components havemelted. The mixture is then cooled to 50° C. with continuous stirring.Methylparaben and propylparaben are added with mixing and the mixture iscooled to ambient temperature. The compound of formula I is added to themixture and blended well.

What is claimed is:
 1. A compound of the formula I

wherein: A¹ is ═N— or ═C(H)—; A² is ═N—, ═C(H)—, or ═C(R′)— wherein R′is halogen, —CN, —Oalkyl, —CO₂alkyl or —SO₂alkyl, wherein the foregoingalkyl moieties are of 1 to 3 carbon atoms; D is ═N—, ═C(R¹)—, ═C(H)—,═C(SO₂R¹)—, ═C(S(O)R¹)—, ═C(C(O)R¹)—, ═C(C(O)H)—, ═C(SR^(1a))—,═C(OR^(1a))— or ═C(NHR^(1a))—,  wherein R¹ is selected from the classconsisting of: (A) —R¹⁰⁰, which is: branched or unbranched alkyl of 1 to6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl orcycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkylor cycloalkenyl group one or more hydrogen atoms are optionally andindependently replaced with: (i) halogen, (ii) oxo, (iii) aryl orheteroaryl which is selected from the class consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:(a) alkyl of 1 to 3 carbon atoms, (b) —COOH, (c) —SO₂OH, (d) —PO(OH)₂,(e) a group of the formula —COOR⁸, wherein R⁸ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) agroup of the formula —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are each independentlya hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁹ and R¹⁰constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,(g) a group of the formula —CONR¹¹R¹², wherein R¹¹ and R¹² are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹¹ and R¹² constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-, (h) a group of the formula —OR¹³,wherein R¹³ is a hydrogen atom, or an alkyl or acyl group of 1 to 7carbon atoms, (i) a group of the formula —SR¹⁴, wherein R¹⁴ is ahydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (j)—CN, or (k) an amidino group of the formula

 wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (l) halogen, (m) a group of the formula —NHCONHalkyl,wherein the alkyl moiety contains 1 to 3 carbon atoms, (n) a group ofthe formula —NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbonatoms, (iv) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, (v) —CN, (vi) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ andR²⁰ are each, independently, a hydrogen atom, alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-, (vii) a group of theformula —OR²¹, wherein R²¹ is a hydrogen atom, or a straight or branchedalkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety contains 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂, (viii) a group of the formula —SR²², wherein R²² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one ormore hydrogen atoms of said alkyl or acyl group are optionally replacedwith a group independently selected from the class consisting of —OH,—Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMeand —NMe₂, (ix) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently, (a) a hydrogen atom, (b) straight or branched alkylor acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,wherein said one or more hydrogen atoms of said alkyl or acyl group areoptionally replaced with a group independently selected from the classconsisting of —OH, —Oalkyl (wherein the alkyl moiety is 1 to 6 carbonatoms), —NH₂, —NHMe and —NMe₂, (c) a group of the formula—(CH₂)_(m)COOH, wherein m is 0, 1 or 2, (d) a group of the formula—(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straight orbranched alkyl of 1 to 6 carbon atoms, or (e) a group of the formula—(CH₂)_(n)CONHR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straightor branched alkyl of 1 to 6 carbon atoms, (x) a quaternary group of theformula

 wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable counter ion, (xi) a saturated, or partiallyunsaturated heterocyclic group consisting of 3 to 7 ring atoms selectedfrom N, O, C and S, including but not limited to imidazolinyl,imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally mono- or polysubstituted with oxo, and (xii) a cycloalkylgroup of 3 to 7 carbon atoms, (B) branched or unbranched carboxylic acidgroups of 3 to 6 carbon atoms, (C) branched or unbranched phosphonicacid groups of 2 to 6 carbon atoms, (D) branched or unbranched sulfonicacid groups of 2 to 6 carbon atoms, (E) amidino groups of the formula

 wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, (F) guanidinogroups of the formula

 wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring, (G) aryl orheteroaryl which is selected from the class consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:(i) alkyl of 1 to 3 carbon atoms, (ii) —COOH, (iii) —SO₂OH, (iv)—PO(OH)₂, (v) a group of the formula —COOR³⁶, wherein R³⁶ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms, (vi) a group of the formula —NR³⁷R³⁸, wherein R³⁷ and R³⁸ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, orwherein R³⁷ and R³⁸ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, (vii) a group of the formula —CONR³⁹R⁴⁰, wherein R³⁹and R⁴⁰ are each, independently, a hydrogen atom, alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R³⁹ and R⁴⁰constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-, (viii) a group of theformula —OR⁴¹, wherein R⁴¹ is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, (ix) a group of the formula —SR⁴², wherein R⁴²is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,(x) —CN, or (xi) an amidino group of the formula

 wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ and R⁴⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ andR⁴⁷ are each independently a hydrogen atom, phenyl which is optionallymono- or polysubstituted with halogen, or R¹⁰⁰, wherein R¹⁰⁰ is ashereinbefore defined, (I) saturated or unsaturated heterocyclic groupsconsisting of 3 to 7 ring atoms selected from N, O, C and S, or bicyclicheterocyclic groups consisting of 8 to 11 atoms selected from N, O, Cand S, including but not limited to imidazolinyl, imidazolidinyl,pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl,tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl,wherein said heterocyclic group is optionally mono- or poly-substitutedwith moieties selected from the class consisting of: (i) oxo, (ii)—OR¹⁰¹, wherein R¹⁰¹ is: (a) a hydrogen atom, (b) alkyl of 1 to 7carbons, wherein any hydrogen atom of said alkyl group is optionallyreplaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is an alkyl moiety of 1 to 6carbon atoms), —NH₂, —NHMe or —NMe₂, (c) acyl of 1 to 7 carbons, whereinany hydrogen atom of said acyl group is optionally replaced with —OH,—OR¹¹¹ (wherein R¹¹¹ is an alkyl moiety of 1 to 6 carbon atoms), —NH₂,—NHMe or —NMe₂, (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are eachindependently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰²and R¹⁰³ constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-,or (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms, (iii)—CONR¹⁰⁵R⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently: (a) ahydrogen atom, (b) straight or branched alkyl of 1 to 7 atoms orcycloalkyl of 3 to 7 atoms, (c) benzoyl, (d) benzyl or (e) phenyl,wherein said phenyl ring is optionally mono- or polysubstituted with—OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbon atoms,  or, wherein R¹⁰⁵and R¹⁰⁶ constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-,(iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight or branchedalkyl of 1 to 7 carbon atoms, (v) straight or branched alkyl of 1 to 7carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkylof 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl,alkenyl, alkynyl or cycloalkyl group is optionally replaced with amoiety independently selected from the class consisting of: (a) oxo, (b)—OH, (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms, (d)—OCOCH₃, (e) —NH₂, (f) —NHMe, (g) —NMe₂, (h) —CO₂H, and (i) —CO₂ R¹¹⁴wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7carbons, (vi) acyl of 1 to 7 carbon atoms, which may be straight,branched or cyclic, and wherein one or more hydrogen atoms of said acylgroup is optionally replaced with a moiety independently selected fromthe class consisting of: (a) —OH, (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1to 6 carbon atoms, (c) —NH₂, (d) —NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo,(h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms, (i) —CN,(j) the halogen atoms, (k) heterocycles selected from the classconsisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, and (l) aryl or heteroaryl selectedfrom the class consisting of phenyl, naphthyl, indolyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is: (a) arylor heteroaryl which is selected from the group consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbonatoms), (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbonatoms), or (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms), (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is: (a)aryl or heteroaryl which is selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,wherein said aryl or heteroaryl moiety is optionally substituted withone or more moieties selected from the class consisting of the halogenatoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹²⁰ (whereinR¹²⁰ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) a heterocyclicgroup selected from the class consisting of imidazolinyl,imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl isoptionally substituted with one or more halogen, straight or branchedalkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of1 to 6 carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms,wherein said alkyl moiety is optionally substituted with one or moremoieties selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²²is hydrogen or alkyl of 1 to 6 carbon atoms), (ix) —CHO, (x) the halogenatoms, and (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, (J) the halogen atoms, and (K) —CN and,wherein R^(1a) is R¹⁰⁰; X is an oxygen or sulfur atom; R³ is: (A) ahydrogen atom, or (B) branched or unbranched alkyl of 1 to 3 carbonatoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl orcycloalkyl group is optionally substituted with: (i) a group of theformula —OR⁴⁸, wherein R⁴⁸ is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, or (ii) a group of the formula —NR⁴⁹R⁵⁰, whereinR⁴⁹ and R⁵⁰ are each, independently, a hydrogen atom, alkyl of 1 to 2carbon atoms, or acyl of 1 to 2 carbon atoms; R⁴ is a group of theformula —(CR⁵¹R⁵²)_(x)(CR⁵³R⁵⁴)_(y)R⁵⁵, wherein, x is 0 or 1, y is 0 or1, R⁵¹, R⁵² and R⁵³ are each, independently: (A) a hydrogen atom, (B) agroup of the formula —OR⁵⁶, wherein R⁵⁶ is a hydrogen atom, or an alkylor acyl group of 1 to 7 carbon atoms, or (C) branched or unbranchedalkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, R⁵⁴is: (A) a group of the formula R⁵⁷, wherein R⁵⁷ is independentlyselected from the same class as is R¹, or (B) a group of the formula—OR⁵⁸, wherein R⁵⁸ is independently selected from the same class as isR¹; R⁵⁵ is: aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more of the hydrogen atomsof said aryl or heteroaryl group is optionally and independentlyreplaced with: (A) R⁵⁹, which is aryl or heteroaryl selected from theclass consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more of the hydrogen atomsof said aryl or heteroaryl group is optionally and independentlyreplaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atomsor cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo, (ii) a group ofthe formula —COOR⁶⁰, wherein R⁶⁰ is straight or branched alkyl of 1 to 5carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (iii) a group of theformula —NR⁶¹R⁶², wherein R⁶¹ and R⁶² are each, independently, ahydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁶¹and R⁶² constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, (iv) a group of the formula —CONR⁶³R⁶⁴, wherein R⁶³ and R⁶⁴ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁶³ andR⁶⁴ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, (v) a group of the formula —OR⁶⁵, wherein R⁶⁵ is a hydrogen atom,or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vi) agroup of the formula —SR⁶⁶, wherein R⁶⁶ is a hydrogen atom, or an alkyl,fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vii) —CN, (viii)nitro, or (ix) halogen, (B) methyl, which is optionally mono- orpolysubstituted with fluorine atoms and additionally is optionallymonosubstituted with R⁵⁹, (C) branched or unbranched alkyl of 2 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl orcycloakyl group is optionally mono- or polysubstituted with halogen oroxo, (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms, (E) a group of the formula —NR⁶⁸R⁶⁹, wherein R⁶⁸ and R⁶⁹ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbonatoms, or wherein R⁶⁸ and R⁶⁹ constitute a saturated hydrocarbon bridgeof 3 to 5 carbon atoms which together with the nitrogen atom betweenthem form a heterocyclic ring, and wherein one of R⁶⁸ and R⁶⁹ mayadditionally be the group R⁵⁹, (F) a group of the formula —CONR⁷⁰R⁷¹,wherein R⁷⁰ and R⁷¹ are each, independently, a hydrogen atom, alkyl orfluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,or wherein R⁷⁰ and R⁷¹ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one of R⁷⁰ and R⁷¹ may additionally bethe group R⁵⁹, (G) a group of the formula —COR⁷², wherein R⁷² is ahydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms,cycloalkyl of 3 to 5 carbon atoms or R⁵⁹, (H) a group of the formula—OR⁷³, wherein R⁷³ is a hydrogen atom, an alkyl, fluoroalkyl or acylgroup of 1 to 7 carbon atoms, or R⁵⁹, (I) a group of the formula —SR⁷⁴,wherein R⁷⁴ is a hydrogen atom, an alkyl fluoroalkyl or acyl group of 1to 7 carbon atoms, or R⁵⁹, (J) —CN, (K) nitro, or (L) halogen; R⁵ is Clor trifluoromethyl; Z is ═N— or ═C(R⁶)— wherein R⁶ is a hydrogen,fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl;and, R⁷ is a hydrogen, fluorine, chlorine, bromine or iodine atom,methyl, —CN, nitro or trifluoromethyl, with the condition that when Z is═N— or ═C(H)—, R⁷ is chlorine, trifluoromethyl, —CN or nitro; or apharmaceutically acceptable salt thereof.
 2. A compound of the formulaI, as set forth in claim 1, wherein: A¹ is ═N— or ═C(H)—; A² is ═N—,═C(H)—, or ═C(R′)— wherein R′ is halogen, —CN, —Oalkyl, —CO₂alkyl or—SO₂alkyl, wherein the foregoing alkyl moieties are of 1 to 3 carbonatoms; D is ═N—, ═C(R¹)—, ═C(H)—, ═C(SO₂R¹)—, ═C(S(O)R¹)—, ═C(C(O)R¹)—,═C(C(O)H)—, ═C(SR^(1a))—, ═C(OR^(1a))— or ═C(NHR^(1a))—,  wherein R¹ isselected from the class consisting of: (A) —R^(100a), which is: branchedor unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbonatoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in whichalkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogenatoms are optionally and independently replaced with: (i) halogen, (ii)oxo, (iii) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:(a) alkyl of 1 to 3 carbon atoms, (b) —COOH, (c) —SO₂OH, (d) —PO(OH)₂,(e) a group of the formula —COOR⁸, wherein R⁸ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) agroup of the formula —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are each independentlya hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁹ and R¹⁰constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,(g) a group of the formula —CONR¹¹R¹², wherein R¹¹ and R¹² are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹¹ and R¹² constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-, (h) a group of the formula —OR¹³,wherein R¹³ is a hydrogen atom, or an alkyl or acyl group of 1 to 7carbon atoms, (i) a group of the formula —SR¹⁴, wherein R¹⁴ is ahydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (j)—CN, or (k) an amidino group of the formula

 wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (l) halogen, (m) a group of the formula —NHCONHalkyl,wherein the alkyl moiety contains 1 to 3 carbon atoms, (n) a group ofthe formula —NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbonatoms, (iv) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, (v) —CN, (vi) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ andR²⁰ are each, independently, a hydrogen atom, alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-, (vii) a group of theformula —OR²¹, wherein R²¹ is a hydrogen atom, or a straight or branchedalkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety contains 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂, (viii) a group of the formula —SR²², wherein R²² is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one ormore hydrogen atoms of said alkyl or acyl group are optionally replacedwith a group independently selected from the class consisting of —OH,—Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMeand —NMe₂, (ix) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently, (a) a hydrogen atom, (b) straight or branched alkylor acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,wherein said one or more hydrogen atoms of said alkyl or acyl group areoptionally replaced with a group independently selected from the classconsisting of —OH, —Oalkyl (wherein the alkyl moiety is 1 to 6 carbonatoms), —NH₂, —NHMe and —NMe₂, (c) a group of the formula—(CH₂)_(m)COOH, wherein m is 0, 1 or 2, (d) a group of the formula—(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straight orbranched alkyl of 1 to 6 carbon atoms, or (e) a group of the formula—(CH₂)_(n)CONHR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straightor branched alkyl of 1 to 6 carbon atoms, (x) a quaternary group of theformula

 wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable counter ion, (xi) a saturated, or partiallyunsaturated heterocyclic group consisting of 3 to 7 ring atoms selectedfrom N, O, C and S, including but not limited to imidazolinyl,imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally mono- or polysubstituted with oxo, and (xii) a cycloalkylgroup of 3 to 7 carbon atoms, (B) branched or unbranched carboxylic acidgroups of 3 to 6 carbon atoms, (C) branched or unbranched phosphonicacid groups of 2 to 6 carbon atoms, (D) branched or unbranched sulfonicacid groups of 2 to 6 carbon atoms, (E) amidino groups of the formula

 wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, (F) guanidinogroups of the formula

 wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring, (G) aryl orheteroaryl which is selected from the class consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of saidaryl or heteroaryl group are optionally and independently replaced with:(i) alkyl of 1 to 3 carbon atoms, (ii) —COOH, (iii) —SO₂OH, (iv)—PO(OH)₂, (v) a group of the formula —COOR³⁶, wherein R³⁶ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms, (vi) a group of the formula —NR³⁷R³⁸, wherein R³⁷ and R³⁸ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, orwherein R³⁷ and R³⁸ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, (vii) a group of the formula —CONR³⁹R⁴⁰, wherein R³⁹and R⁴⁰ are each, independently, a hydrogen atom, alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R³⁹ and R⁴⁰constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one carbon atom in said hydrocarbon bridge is optionallyreplaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-, (viii) a group of theformula —OR⁴¹, wherein R⁴¹ is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, (ix) a group of the formula —SR⁴², wherein R⁴²is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,(x) —CN, or (xi) an amidino group of the formula

 wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ and R⁴⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ andR⁴⁷ are each independently a hydrogen atom, phenyl which is optionallymono-or polysubstituted with halogen, or R^(100a), wherein R^(100a) isas hereinbefore defined, (I) saturated or unsaturated heterocyclicgroups consisting of 3 to 7 ring atoms selected from N, O, C and S, orbicyclic heterocyclic groups consisting of 8 to 11 atoms selected fromN, O, C and S, including but not limited to imidazolinyl,imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally mono- or poly-substituted with moieties independentlyselected from the class consisting of: (i) oxo, (ii) —OR¹⁰¹, whereinR¹⁰¹ is: (a) a hydrogen atom, (b) alkyl of 1 to 7 carbons, wherein anyhydrogen atom of said alkyl group is optionally replaced with —OH,—OR¹¹⁰ (wherein R¹¹⁰ is an alkyl moiety of 1 to 6 carbon atoms), —NH₂,—NHMe or —NMe₂, (c) acyl of 1 to 7 carbons, wherein any hydrogen atom ofsaid acyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ isan alkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, (d)—CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently a hydrogenatom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—S—, S(O)—, SO₂—, —NH—, or —NMe-, or (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkylof 1 to 7 atoms, (iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are eachindependently: (a) a hydrogen atom, (b) straight or branched alkyl of 1to 7 atoms or cycloalkyl of 3 to 7 atoms, (c) benzoyl, (d) benzyl or (e)phenyl, wherein said phenyl ring is optionally mono- or polysubstitutedwith —OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbon atoms,  or, whereinR¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —S—, S(O)—, SO₂—, —NH—, or —NMe-,(iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, or straight or branchedalkyl of 1 to 7 carbon atoms, (v) straight or branched alkyl of 1 to 7carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkylof 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl,alkenyl, alkynyl or cycloalkyl group is optionally replaced with amoiety independently selected from the class consisting of: (a) oxo, (b)—OH, (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms, (d)—OCOCH₃, (e) —NH₂, (f) —NHMe, (g) —NMe₂, (h) —CO₂H, and (i) —CO₂ R¹¹⁴wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7carbons, (vi) acyl of 1 to 7 carbon atoms, which may be straight,branched or cyclic, and wherein one or more hydrogen atoms of said acylgroup is optionally replaced with a moiety independently selected fromthe class consisting of: (a) —OH, (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1to 6 carbon atoms, (c) —NH₂, (d) —NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo,(h) —CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms, (i) —CN,(j) the halogen atoms, (k) heterocycles selected from the classconsisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, and (l) aryl or heteroaryl selectedfrom the class consisting of phenyl, naphthyl, indolyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is: (a) arylor heteroaryl which is selected from the group consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbonatoms), (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbonatoms), or (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms), (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is: (a)aryl or heteroaryl which is selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,wherein said aryl or heteroaryl moiety is optionally substituted withone or more moieties selected from the class consisting of the halogenatoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹²⁰ (whereinR¹²⁰ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) a heterocyclicgroup selected from the class consisting of imidazolinyl,imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl isoptionally substituted with one or more halogen, straight or branchedalkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of1 to 6 carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms,wherein said alkyl moiety is optionally substituted with one or moremoieties selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²²is hydrogen or alkyl of 1 to 6 carbon atoms), (ix) —CHO, (x) the halogenatoms, and (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, (J) the halogen atoms, and (K) —CN and,wherein R^(1a) is R^(100a); X is an oxygen or sulfur atom; R³ is: (A) ahydrogen atom, or (B) branched or unbranched alkyl of 1 to 3 carbonatoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl orcycloalkyl group is optionally substituted with: (i) a group of theformula —OR⁴⁸, wherein R⁴⁸ is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, or (ii) a group of the formula —NR⁴⁹R⁵⁰, whereinR⁴⁹ and R⁵⁰ are each, independently, a hydrogen atom, alkyl of 1 to 2carbon atoms, or acyl of 1 to 2 carbon atoms; R⁴ is a group of theformula —CH₂R⁵⁵, wherein, R⁵⁵ is: aryl or heteroaryl which is selectedfrom the class consisting of phenyl, naphthyl, indolyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more of the hydrogen atomsof said aryl or heteroaryl group is optionally and independentlyreplaced with: (A) R^(59a), which is aryl or heteroaryl selected fromthe class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein one or more of the hydrogen atomsof said aryl or heteroaryl group is optionally and independentlyreplaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atomsor cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group isoptionally mono- or polysubstituted with halogen or oxo, (ii) a group ofthe formula —COOR⁶⁰, wherein R⁶⁰ is straight or branched alkyl of 1 to 5carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (iii) a group of theformula —NR⁶¹R⁶², wherein R⁶¹ and R⁶² are each, independently, ahydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁶¹and R⁶² constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, (iv) a group of the formula —CONR⁶³R⁶⁴, wherein R⁶³ and R⁶⁴ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁶³ andR⁶⁴ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, (v) a group of the formula —OR⁶⁵, wherein R⁶⁵ is a hydrogen atom,or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vi) agroup of the formula —SR⁶⁶, wherein R⁶⁶ is a hydrogen atom, or an alkyl,fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vii) —CN, (viii)nitro, or (ix) halogen, (B) methyl, which is optionally mono- orpolysubstituted with fluorine atoms and additionally is optionallymonosubstituted with R^(59a), (C) branched or unbranched alkyl of 2 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl orcycloakyl group is optionally mono- or polysubstituted with halogen oroxo, (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms, (E) a group of the formula —NR⁶⁸R⁶⁹, wherein R⁶⁸ and R⁶⁹ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbonatoms, or wherein R⁶⁸ and R⁶⁹ constitute a saturated hydrocarbon bridgeof 3 to 5 carbon atoms which together with the nitrogen atom betweenthem form a heterocyclic ring, and wherein one of R⁶⁸ and R⁶⁹ mayadditionally be the group R^(59a), (F) a group of the formula—CONR⁷⁰R⁷¹, wherein R⁷⁰ and R⁷¹ are each, independently, a hydrogenatom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to6 carbon atoms, or wherein R⁷⁰ and R⁷¹ constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom between them form a heterocyclic ring, and wherein one ofR⁷⁰ and R⁷¹ may additionally be the group R^(59a), (G) a group of theformula —COR⁷², wherein R⁷² is a hydrogen atom, straight or branchedalkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms orR^(59a), (H) a group of the formula —OR⁷³, wherein R⁷³ is a hydrogenatom, an alkyl fluoroalkyl or acyl group of 1 to 7 carbon atoms, orR^(59a), (I) a group of the formula —SR⁷⁴, wherein R⁷⁴ is a hydrogenatom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, orR^(59a), (J) —CN, (K) nitro, or (L) halogen; R⁵ is Cl ortrifluoromethyl; Z is ═N— or ═C(R⁶)— wherein R⁶ is a hydrogen, fluorine,chlorine, bromine or iodine atom, methyl or trifluoromethyl; and, R⁷ isa hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, —CN,nitro or trifluoromethyl, with the condition that when Z is ═N— or═C(H)—, R⁷ is chlorine, trifluoromethyl, —CN or nitro; or apharmaceutically acceptable salt thereof.
 3. A compound of the formulaI, as set forth in claim 1, wherein: A¹ is ═N— or ═C(H)—; A² is ═N—, or═C(H)—; D is ═N—, ═C(R¹)—, ═C(H)—, ═C(SO₂R¹)—, ═C(C(O)H)— or═C(C(O)R¹)—, wherein R¹ is selected from the class consisting of: (A)—R^(100b), which is: branched or unbranched alkyl of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenylgroup one or more hydrogen atoms are optionally and independentlyreplaced with: (i) oxo, (ii) phenyl, wherein one hydrogen atom of saidphenyl group is optionally replaced with: (a) alkyl of 1 to 3 carbonatoms, (b) —COOH, (c) —SO₂₀H, (d) —PO(OH)₂, (e) a group of the formula—COOR⁸, wherein R⁸ is straight or branched alkyl of 1 to 5 carbon atomsor cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula—NR⁹R¹⁰, wherein R⁹ and R¹⁰ are each independently a hydrogen atom,alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acylof 1 to 7 carbon atoms, or wherein R⁹ and R¹⁰ constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom between them form a heterocyclic ring, (g) a group of theformula —CONR¹¹R¹², wherein R¹¹ and R¹² are each independently ahydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6carbon atoms, or wherein R¹¹ and R¹² constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe-,(h) a group of the formula —OR¹³, wherein R¹³ is a hydrogen atom, or analkyl or acyl group of 1 to 7 carbon atoms, (i) a group of the formula—SR¹⁴, wherein R¹⁴ is a hydrogen atom, or an alkyl or acyl group of 1 to7 carbon atoms, (j) —CN, or (k) an amidino group of the formula

 wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (l) a group of the formula —NHCONHalkyl, wherein thealkyl moiety contains 1 to 3 carbon atoms, (m) a group of the formula—NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,(iii) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, (iv) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-, (v) a group of the formula —OR²¹, wherein R²¹ is ahydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7carbon atoms, wherein one or more hydrogen atoms of said alkyl or acylgroup are optionally replaced with a group independently selected fromthe class consisting of —OH, —Oalkyl (wherein the alkyl moiety contains1 to 6 carbon atoms), —NH₂, —NHMe and —NMe₂, (vi) a group of the formula—NR²³R²⁴, wherein R²³ and R²⁴ are each, independently, (a) a hydrogenatom, (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂, (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2, (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or 2,and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms, or(e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1 or 2,and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,(vii) a quaternary group of the formula

 wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ a pharmaceuticallyacceptable counter ion, or (viii) a cycloalkyl group of 3 to 7 carbonatoms, (B) branched or unbranched carboxylic acid groups of 3 to 6carbon atoms, (C) branched or unbranched phosphonic acid groups of 2 to6 carbon atoms, (D) branched or unbranched sulfonic acid groups of 2 to6 carbon atoms, (E) amidino groups of the formula

 wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, (F) guanidinogroups of the formula

 wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring, (G) phenyl,wherein one or more hydrogen atoms of said phenyl group are optionallyand independently replaced with: (i) alkyl of 1 to 3 carbon atoms, (ii)—COOH, (iii) —SO₂OH, (iv) —PO(OH)₂, (v) a group of the formula —COOR³⁶,wherein R³⁶ is straight or branched alkyl of 1 to 5 carbon atoms orcycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula —NR³⁷R³⁸,wherein R³⁷ and R³⁸ are each, independently, a hydrogen atom, alkyl of 1to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7carbon atoms, or wherein R³⁷ and R³⁸ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, (vii) a group of the formula—CONR³⁹R⁴⁰, wherein R³⁹ and R⁴⁰ are each, independently, a hydrogenatom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,or wherein R³⁹ and R⁴⁰ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (viii) a group ofthe formula —OR⁴¹, wherein R⁴¹ is a hydrogen atom, or an alkyl or acylgroup of 1 to 7 carbon atoms, (ix) a group of the formula —SR⁴², whereinR⁴² is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbonatoms, (x) —CN, or (xi) an amidino group of the formula

 wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ and R⁴⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ andR⁴⁷ are each independently a hydrogen atom, phenyl which is optionallymono-or polysubstituted with halogen, or R^(100b), wherein R^(100b) isas hereinbefore defined, (I) saturated or unsaturated heterocyclicgroups selected from the class consisting of imidazolinyl,imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally mono- or poly-substituted with moieties independentlyselected from the class consisting of: (i) oxo, (ii) —OR¹⁰¹, whereinR¹⁰¹ is: (a) a hydrogen atom, (b) alkyl of 1 to 7 carbons, wherein anyhydrogen atom of said alkyl group is optionally replaced with —OH,—OR¹¹⁰ (wherein R¹¹⁰ is an alkyl moiety of 1 to 6 carbon atoms), —NH₂,—NHMe or —NMe₂, (c) acyl of 1 to 7 carbons, wherein any hydrogen atom ofsaid acyl group is optionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ isan alkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, (d)—CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are each independently a hydrogenatom or alkyl of 1 to 7 atoms, or wherein R¹⁰² and R¹⁰³ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-, or (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms,(iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently: (a) ahydrogen atom, (b) straight or branched alkyl of 1 to 7 atoms orcycloalkyl of 3 to 7 atoms, (c) benzoyl, (d) benzyl or (e) phenyl,wherein said phenyl ring is optionally mono- or polysubstituted with—OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbon atoms,  or, wherein R¹⁰⁵and R¹⁰⁶ constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (iv) —COOR¹⁰⁷,wherein R¹⁰⁷ is a hydrogen atom, or straight or branched alkyl of 1 to 7carbon atoms, (v) straight or branched alkyl of 1 to 7 carbon atoms,alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl,alkynyl or cycloalkyl group is optionally replaced with a moietyindependently selected from the class consisting of: (a) oxo, (b) —OH,(c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms, (d) —OCOCH₃,(e) —NH₂, (f) —NHMe, (g) —NMe₂, (h) —CO₂H, and (i) —CO₂ R¹¹⁴ whereinR¹¹⁴ is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched orcyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of: (a) —OH, (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6carbon atoms, (c) —NH₂, (d) —NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo, (h)—CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms, (i) —CN, (j)the halogen atoms, (k) heterocycles selected from the class consistingof imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, and (l) aryl or heteroaryl selectedfrom the class consisting of phenyl, naphthyl, indolyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is: (a) arylor heteroaryl which is selected from the group consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbonatoms), (b) a heterocyclic group selected from the class consisting ofimidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group isoptionally substituted with one or more moieties selected from the classconsisting of the halogen atoms, straight or branched alkyl of 1 to 6carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbonatoms), or (c) straight or branched alkyl of 1 to 7 atoms, wherein saidalkyl moiety is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms), (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is: (a)aryl or heteroaryl which is selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,wherein said aryl or heteroaryl moiety is optionally substituted withone or more moieties selected from the class consisting of the halogenatoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹²⁰ (whereinR¹²⁰ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) a heterocyclicgroup selected from the class consisting of imidazolinyl,imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl,tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl,tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl isoptionally substituted with one or more halogen, straight or branchedalkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of1 to 6 carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms,wherein said alkyl moiety is optionally substituted with one or moremoieties selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²²is hydrogen or alkyl of 1 to 6 carbon atoms), (ix) —CHO, (x) the halogenatoms, and (xi) aryl or heteroaryl which is selected from the classconsisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl, (J) the halogen atoms, and (K) —CN; X is anoxygen atom; R³ is branched or unbranched alkyl of 1 to 3 carbon atoms;R⁴ is a group of the formula —CH₂R⁵⁵, wherein, R⁵⁵ is: aryl orheteroaryl which is selected from the class consisting of phenyl,pyridyl, and pyrimidinyl, wherein one or more of the hydrogen atoms ofsaid aryl or heteroaryl group is optionally and independently replacedwith: (A) R^(59b), which is aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, and thiazolyl, wherein one of the hydrogen atoms of said arylor heteroaryl group is optionally replaced with: (i) branched orunbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, which alkyl or cycloakyl group is optionally mono- orpolysubstituted with halogen or oxo, (ii) —CN, (iii) nitro, or (iv)halogen, (B) methyl, which is optionally trisubstituted with fluorineatoms or is optionally monosubstituted with R^(59b), (C) branched orunbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, which alkyl or cycloakyl group is optionally monosubstituted withhalogen or oxo, (D) a group of the formula —COOR⁶⁷, wherein R⁶⁷ isstraight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to5 carbon atoms, (E) a group of the formula —COR⁷², wherein R⁷² is ahydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms,cycloalkyl of 3 to 5 carbon atoms or R^(59b), (F) a group of the formula—OR⁷³, wherein R⁷³ is a hydrogen atom, an alkyl, fluoroalkyl or acylgroup of 1 to 7 carbon atoms, or R^(59b), (G) —CN, (H) nitro, or (I)halogen; R⁵ is Cl; Z is ═C(H)—; and, R⁷ is Cl; or a pharmaceuticallyacceptable salt thereof.
 4. A compound of the formula I, as set forth inclaim 1, wherein: A¹ is ═N—; A² is ═C(H)—; D is ═C(R¹)—, ═C(H)—,═C(SO₂R¹)—, ═C(C(O)H)— or ═C(COR¹)—, wherein R¹ is selected from theclass consisting of: (A) —R^(100c), which is: branched or unbranchedalkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms orcycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl,alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms areoptionally and independently replaced with: (i) oxo, (ii) phenyl,wherein one hydrogen atom of said phenyl group is optionally replacedwith: (a) alkyl of 1 to 3 carbon atoms, (b) —COOH, (c) —SO₂₀H, (d)—PO(OH)₂, (e) a group of the formula —COOR⁸, wherein R⁸ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms, (f) a group of the formula —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁹ andR¹⁰ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, (g) a group of the formula —CONR¹¹R¹², wherein R¹¹ and R¹² areeach independently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹¹ and R¹² constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-, (h) a group of the formula —OR¹³, wherein R¹³ is ahydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, (i) agroup of the formula —SR¹⁴, wherein R¹⁴ is a hydrogen atom, or an alkylor acyl group of 1 to 7 carbon atoms, (j) —CN, or (k) an amidino groupof the formula

 wherein R¹⁵, R¹⁶ and R¹⁷ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹⁵, R¹⁶ and R¹⁷ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (l) a group of the formula —NHCONHalkyl, wherein thealkyl moiety contains 1 to 3 carbon atoms, (m) a group of the formula—NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,(iii) a group of the formula —COOR¹⁸, wherein R¹⁸ is straight orbranched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, (iv) a group of the formula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ areeach, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁹ and R²⁰ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-, (v) a group of the formula —OR²¹, wherein R²¹ is ahydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7carbon atoms, wherein one or more hydrogen atoms of said alkyl or acylgroup are optionally replaced with a group independently selected fromthe class consisting of —OH, —Oalkyl (wherein the alkyl moiety contains1 to 6 carbon atoms), —NH₂, —NHMe and —NMe₂, (vi) a group of the formula—NR²³R²⁴, wherein R²³ and R²⁴ are each, independently, (a) a hydrogenatom, (b) straight or branched alkyl or acyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogenatoms of said alkyl or acyl group are optionally replaced with a groupindependently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety is 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂, (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2, (d) a group of the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or 2,and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms, or(e) a group of the formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1 or 2,and wherein R²⁵ is straight or branched alkyl of 1 to 6 carbon atoms,(vii) a quaternary group of the formula

 wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable, or (viii) a cycloalkyl group of 3 to 7carbon atoms, (B) branched or unbranched carboxylic acid groups of 3 to6 carbon atoms, (C) branched or unbranched phosphonic acid groups of 2to 6 carbon atoms, (D) branched or unbranched sulfonic acid groups of 2to 6 carbon atoms, (E) amidino groups of the formula

 wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, (F) guanidinogroups of the formula

 wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring, (G) phenyl,wherein one or more hydrogen atoms of said phenyl group are optionallyand independently replaced with: (i) alkyl of 1 to 3 carbon atoms, (ii)—COOH, (iii) —SO₂OH, (iv) —PO(OH)₂, (v) a group of the formula —COOR³⁶,wherein R³⁶ is straight or branched alkyl of 1 to 5 carbon atoms orcycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula —NR³⁷R³⁸,wherein R³⁷ and R³⁸ are each, independently, a hydrogen atom, alkyl of 1to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7carbon atoms, or wherein R³⁷ and R³⁸ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, (vii) a group of the formula—CONR³⁹R⁴⁰, wherein R³⁹ and R⁴⁰ are each, independently, a hydrogenatom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,or wherein R³⁹ and R⁴⁰ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (viii) a group ofthe formula —OR⁴¹, wherein R⁴¹ is a hydrogen atom, or an alkyl or acylgroup of 1 to 7 carbon atoms, (ix) a group of the formula —SR⁴², whereinR⁴² is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbonatoms, (x) —CN, or (xi) an amidino group of the formula

 wherein R⁴³, R⁴⁴ and R⁴⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and wherein two of R⁴³, R⁴⁴ and R⁴⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (H) groups of the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ andR⁴⁷ are each independently a hydrogen atom, phenyl which is optionallymonosubstituted with halogen, or R^(100c), wherein R^(100c) is ashereinbefore defined, (I) saturated or unsaturated heterocyclic groupsselected from the class consisting of pyrrolinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein saidheterocyclic groups are optionally mono- or poly-substituted withmoieties independently selected from the class consisting of: (i) oxo,(ii) —OR¹⁰¹, wherein R¹⁰¹ is: (a) a hydrogen atom, (b) alkyl of 1 to 7carbons, wherein any hydrogen atom of said alkyl group is optionallyreplaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is an alkyl moiety of 1 to 6carbon atoms), —NH₂, —NHMe or —NMe₂, (c) acyl of 1 to 7 carbons, whereinany hydrogen atom of said acyl group is optionally replaced with —OH,—OR¹¹¹ (wherein R¹¹¹ is an alkyl moiety of 1 to 6 carbon atoms), —NH₂,—NHMe or —NMe₂, (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are eachindependently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰²and R¹⁰³ constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, or (e) —COOR¹⁰⁴,wherein R¹⁰⁴ is alkyl of 1 to 7 atoms, (iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵and R¹⁰⁶ are each independently: (a) a hydrogen atom, (b) straight orbranched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms, (c)benzoyl, (d) benzyl or (e) phenyl, wherein said phenyl ring isoptionally mono- or polysubstituted with —OR¹¹², wherein R¹¹² is alkylof 1 to 6 carbon atoms,  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-, (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, orstraight or branched alkyl of 1 to 7 carbon atoms, (v) straight orbranched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or morehydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group isoptionally replaced with a moiety independently selected from the classconsisting of: (a) oxo, (b) —OH, (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1to 6 carbon atoms, (d) —OCOCH₃, (e) —NH₂, (f) —NHMe, (g) —NMe₂, (h)—CO₂H, and (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms,or cycloalkyl of 3 to 7 carbons, (vi) acyl of 1 to 7 carbon atoms, whichmay be straight, branched or cyclic, and wherein one or more hydrogenatoms of said acyl group is optionally replaced with a moietyindependently selected from the class consisting of: (a) —OH, (b)—OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms, (c) —NH₂, (d)—NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo, (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ isalkyl of 1 to 3 carbon atoms, (i) —CN, (j) the halogen atoms, (k)heterocycles selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and (l) arylor heteroaryl selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl, (vii) —SO₂R¹⁰⁸,wherein R¹⁰⁸ is: (a) aryl or heteroaryl which is selected from the groupconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl thiazolyl and pyrazolyl, wherein said aryl or heteroaryl moietyis optionally substituted with one or more moieties selected from theclass consisting of the halogen atoms, straight or branched alkyl of 1to 6 carbons, and —OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6carbon atoms), (b) a heterocyclic group selected from the classconsisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, wherein said heterocyclic group is optionallysubstituted with one or more moieties selected from the class consistingof the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and—OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbon atoms), or(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkylmoiety is optionally substituted with one or more moieties selected fromthe class consisting of the halogen atoms, straight or branched alkyl of1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogen or alkyl of 1 to 6carbon atoms), (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is: (a) aryl or heteroarylwhich is selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl andpyrazolyl, wherein said aryl or heteroaryl moiety is optionallysubstituted with one or more moieties selected from the class consistingof the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and—OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) aheterocyclic group selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein saidheterocyclyl is optionally substituted with one or more halogen,straight or branched alkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ ishydrogen or alkyl of 1 to 6 carbon atoms), or (c) straight or branchedalkyl of 1 to 7 atoms, wherein said alkyl moiety is optionallysubstituted with one or more moieties selected from the class consistingof the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and—OR¹²² (wherein R¹²² is hydrogen or alkyl of 1 to 6 carbon atoms), (ix)—CHO, (x) the halogen atoms, and (xi) aryl or heteroaryl which isselected from the class consisting of phenyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyland imidazolyl, (J) the halogen atoms, and (K) —CN; X is an oxygen atom;R³ is branched or unbranched alkyl of 1 to 3 carbon atoms; R⁴ is a groupof the formula —CH₂R⁵⁵, wherein, R⁵⁵ is: phenyl, which is optionallysubstituted at the 4-position with: (A) R^(59c), which is aryl orheteroaryl selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl and furyl, wherein one of the hydrogen atoms ofsaid aryl or heteroaryl group is optionally replaced with: (i) branchedor unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6carbon atoms, which alkyl or cycloakyl group is optionally mono- orpolysubstituted with halogen or oxo, (ii) —CN, (iii) nitro, or (iv)halogen, (B) methyl, (C) branched or unbranched alkyl of 2 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakylgroup is optionally monosubstituted with halogen or oxo, (D) a group ofthe formula —COOR⁶⁷, wherein R⁶⁷ is straight or branched alkyl of 1 to 5carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) a group of theformula —COR⁷², wherein R⁷² is a hydrogen atom, straight or branchedalkyl of 1 to 5 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms, (F)a group of the formula —OR⁷³, wherein R⁷³ is a hydrogen atom, an alkyl,or fluoroalkyl or acyl group of 1 to 7 carbon atoms, (G) —CN, (H) nitro,or (I) halogen; R⁵ is Cl; Z is ═C(H)—; and, R⁷ is Cl; or apharmaceutically acceptable salt thereof.
 5. A compound of the formulaI, as set forth in claim 1, wherein: A¹ is ═N—; A² is ═C(H)—; D is═C(H)—, ═C(SO₂R¹)— or ═C(C(O)R¹)—, wherein R¹ is selected from the classconsisting of: (A) —R^(100d), which is: branched or unbranched alkyl of1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl orcycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkylor cycloalkenyl group one or more hydrogen atoms are optionally andindependently replaced with: (i) oxo, (ii) a group of the formula—COOR¹⁸, wherein R¹⁸ is straight or branched alkyl of 1 to 7 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, (iii) a group of the formula—CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ are each, independently, a hydrogenatom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,or wherein R¹⁹ and R²⁰ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (iv) a group ofthe formula —OR²¹, wherein R²¹ is a hydrogen atom, or a straight orbranched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or morehydrogen atoms of said alkyl or acyl group are optionally replaced witha group independently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety contains 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂, (v) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently, (a) a hydrogen atom, (b) straight or branched alkylor acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,wherein said one or more hydrogen atoms of said alkyl or acyl group areoptionally replaced with a group independently selected from the classconsisting of —OH, —Oalkyl (wherein the alkyl moiety is 1 to 6 carbonatoms), —NH₂, —NHMe and —NMe₂, (c) a group of the formula—(CH₂)_(m)COOH, wherein m is 0, 1 or 2, (d) a group of the formula—(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straight orbranched alkyl of 1 to 6 carbon atoms, or (e) a group of the formula—(CH₂)_(n)CONHR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straightor branched alkyl of 1 to 6 carbon atoms, (vi) a quaternary group of theformula

 wherein R²⁶, R²⁷ and R²⁸ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is apharmaceutically acceptable counter ion, or (vii) a cycloalkyl group of3 to 7 carbon atoms, (B) branched or unbranched carboxylic acid groupsof 3 to 6 carbon atoms, (C) branched or unbranched phosphonic acidgroups of 2 to 6 carbon atoms, (D) branched or unbranched sulfonic acidgroups of 2 to 6 carbon atoms, (E) amidino groups of the formula

 wherein r is 2, 3, 4, 5 or 6, and R²⁹, R³⁰ and R³¹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁹, R³⁰ and R³¹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, (F) guanidinogroups of the formula

 wherein s is 2, 3, 4, 5 or 6, and R³², R³³, R³⁴ and R³⁵ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R³², R³³, R³⁴ and R³⁵ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring, (G) groupsof the formula —NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are each independently ahydrogen atom, phenyl which is optionally monosubstituted with halogen,or R^(100d), wherein R^(100d) is as hereinbefore defined, (H) saturatedor unsaturated heterocyclic groups selected from the class consisting ofpyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, wherein said heterocyclic groups are optionally mono-or poly-substituted with moieties independently selected from the classconsisting of: (i) oxo, (ii) —OR¹⁰¹, wherein R¹⁰¹ is: (a) a hydrogenatom, (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, (c) acyl of1 to 7 carbons, wherein any hydrogen atom of said acyl group isoptionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is an alkyl moiety of1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, (d) —CONR¹⁰²R¹⁰³, whereinR¹⁰² and R¹⁰³ are each independently a hydrogen atom or alkyl of 1 to 7atoms, or wherein R¹⁰² and R¹⁰³ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe—,or (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms, (iii)—CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently: (a) ahydrogen atom, (b) straight or branched alkyl of 1 to 7 atoms orcycloalkyl of 3 to 7 atoms, (c) benzoyl, (d) benzyl or (e) phenyl,wherein said phenyl ring is optionally mono- or polysubstituted with—OR¹¹², wherein R¹¹² is alkyl of 1 to 6 carbon atoms,  or, wherein R¹⁰⁵and R¹⁰⁶ constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (iv) —COOR¹⁰⁷,wherein R¹⁰⁷ is a hydrogen atom, or straight or branched alkyl of 1 to 7carbon atoms, (v) straight or branched alkyl of 1 to 7 carbon atoms,alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl,alkynyl or cycloalkyl group is optionally replaced with a moietyindependently selected from the class consisting of: (a) oxo, (b) —OH,(c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms, (d) —OCOCH₃,(e) —NH₂, (f) —NHMe, (g) —NMe₂, (h) —CO₂H, and (i) —CO₂ R¹¹⁴ whereinR¹¹⁴ is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched orcyclic, and wherein one or more hydrogen atoms of said acyl group isoptionally replaced with a moiety independently selected from the classconsisting of: (a) —OH, (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6carbon atoms, (c) —NH₂, (d) —NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo, (h)—CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms, (i) —CN, (j)the halogen atoms, (k) heterocycles selected from the class consistingof pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, and (l) aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyland oxazolyl, (vii) —SO₂R¹⁸, wherein R¹⁰⁸ is: (a) aryl or heteroarylwhich is selected from the group consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl thiazolyl and pyrazolyl,wherein said aryl or heteroaryl moiety is optionally substituted withone or more moieties selected from the class consisting of the halogenatoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁷ (whereinR¹¹⁷ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) a heterocyclicgroup selected from the class consisting of pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclicgroup is optionally substituted with one or more moieties selected fromthe class consisting of the halogen atoms, straight or branched alkyl of1 to 6 carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms,wherein said alkyl moiety is optionally substituted with one or moremoieties selected from the class consisting of the halogen atoms,straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹is hydrogen or alkyl of 1 to 6 carbon atoms), (viii) —COR¹⁰⁹, whereinR¹⁰⁹ is: (a) aryl or heteroaryl which is selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl and pyrazolyl, wherein said aryl or heteroarylmoiety is optionally substituted with one or more moieties selected fromthe class consisting of the halogen atoms, straight or branched alkyl of1 to 6 carbons, and —OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6carbon atoms), (b) a heterocyclic group selected from the classconsisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, wherein said heterocyclyl is optionally substitutedwith one or more halogen, straight or branched alkyl of 1 to 6 carbons,or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of 1 to 6 carbon atoms), or(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkylmoiety is optionally substituted with one or more moieties selected fromthe class consisting of the halogen atoms, straight or branched alkyl of1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogen or alkyl of 1 to 6carbon atoms), (ix) —CHO, (x) the halogen atoms, and (xi) aryl orheteroaryl which is selected from the class consisting of phenyl,thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl,pyrazolyl, isoxazolyl and imidazolyl, and (I) the halogen atoms, X is anoxygen atom; R³ is branched or unbranched alkyl of 1 to 3 carbon atoms;R⁴ is a group of the formula —CH₂R⁵⁵, wherein, R⁵⁵ is: phenyl, which isoptionally substituted at the 4-position with: (A) R^(59d), which isaryl or heteroaryl selected from the class consisting of phenyl,thiophenyl, pyridyl, pyrimidinyl and furyl, wherein one of the hydrogenatoms of said aryl or heteroaryl group is optionally replaced with: (i)branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- orpolysubstituted with halogen or oxo, (ii) —CN, (iii) nitro, or (iv)halogen, (B) methyl, (C) branched or unbranched alkyl of 2 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakylgroup is optionally monosubstituted with halogen or oxo, (D) a group ofthe formula —COOR⁶⁷, wherein R⁶⁷ is straight or branched alkyl of 1 to 5carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) a group of theformula —COR⁷², wherein R⁷² is a hydrogen atom, straight or branchedalkyl of 1 to 5 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms, (F)a group of the formula —OR⁷³, wherein R⁷³ is a hydrogen atom, an alkyl,or fluoroalkyl or acyl group of 1 to 7 carbon atoms, (G) —CN, (H) nitro,or (I) halogen; R⁵ is Cl; Z is ═C(H)—; and, R⁷ is Cl; or apharmaceutically acceptable salt thereof.
 6. A compound of the formulaI, as set forth in claim 1, wherein: A¹ is ═N—; A² is ═C(H)—; D is═C(SO₂R¹)— or ═C(C(O)R¹)—, wherein R¹ is selected from the classconsisting of: (A) —R^(100e), which is: branched or unbranched alkyl of1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl orcycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkylor cycloalkenyl group one or more hydrogen atoms are optionally andindependently replaced with: (i) oxo, (ii) a group of the formula—COOR¹⁸, wherein R¹⁸ is straight or branched alkyl of 1 to 7 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, (iii) a group of the formula—CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ are each, independently, a hydrogenatom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,or wherein R¹⁹ and R²⁰ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (iv) a group ofthe formula —OR²¹, wherein R²¹ is a hydrogen atom, or a straight orbranched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or morehydrogen atoms of said alkyl or acyl group are optionally replaced witha group independently selected from the class consisting of —OH, —Oalkyl(wherein the alkyl moiety contains 1 to 6 carbon atoms), —NH₂, —NHMe and—NMe₂, or (v) a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ areeach, independently, (a) a hydrogen atom, (b) straight or branched alkylor acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,wherein said one or more hydrogen atoms of said alkyl or acyl group areoptionally replaced with a group independently selected from the classconsisting of —OH, —Oalkyl (wherein the alkyl moiety is 1 to 6 carbonatoms), —NH₂, —NHMe and —NMe₂, (c) a group of the formula—(CH₂)_(m)COOH, wherein m is 0, 1 or 2, (d) a group of the formula—(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straight orbranched alkyl of 1 to 6 carbon atoms, or (e) a group of the formula—(CH₂)_(n)CONHR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵ is straightor branched alkyl of 1 to 6 carbon atoms, (B) groups of the formula—NR⁴⁶R⁴⁷, wherein R⁴⁶ and R⁴⁷ are each independently a hydrogen atom,phenyl which is optionally monosubstituted with halogen, or R^(100e),wherein R^(100e) is as hereinbefore defined, and (C) saturated orunsaturated heterocyclic groups selected from the class consisting ofpyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, wherein said heterocyclic groups are optionally mono-or poly-substituted with moieties independently selected from the classconsisting of: (i) oxo, (ii) —OR¹⁰¹, wherein R¹⁰¹ is: (a) a hydrogenatom, (b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of saidalkyl group is optionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is analkyl moiety of 1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, (c) acyl of1 to 7 carbons, wherein any hydrogen atom of said acyl group isoptionally replaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is an alkyl moiety of1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, (d) —CONR¹⁰²R¹⁰³, whereinR¹⁰² and R¹⁰³ are each independently a hydrogen atom or alkyl of 1 to 7atoms, or wherein R¹⁰² and R¹⁰³ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe-,or (e) —COOR¹⁰⁴, wherein R¹⁰⁴ is alkyl of 1 to 7 atoms, (iii)—CONR¹⁰⁵R⁰⁶, wherein R¹⁰⁵ and R¹⁰⁶ are each independently: (a) ahydrogen atom, or (b) straight or branched alkyl of 1 to 7 atoms orcycloalkyl of 3 to 7 atoms,  or, wherein R¹⁰⁵ and R¹⁰⁶ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, and wherein onecarbon atom in said hydrocarbon bridge is optionally replaced by —O—,—NH—, or —NMe-, (iv) —COOR¹⁰⁷, wherein R¹⁰⁷ is a hydrogen atom, orstraight or branched alkyl of 1 to 7 carbon atoms, (v) straight orbranched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or morehydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group isoptionally replaced with a moiety independently selected from the classconsisting of: (a) oxo, (b) —OH, (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1to 6 carbon atoms, (d) —OCOCH₃, (e) —NH₂, (f) —NHMe, (g) —NMe₂, (h)—CO₂H, and (i) —CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms,or cycloalkyl of 3 to 7 carbons, (vi) acyl of 1 to 7 carbon atoms, whichmay be straight, branched or cyclic, and wherein one or more hydrogenatoms of said acyl group is optionally replaced with a moietyindependently selected from the class consisting of: (a) —OH, (b)—OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms, (c) —NH₂, (d)—NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo, (h) —CO₂ R¹¹⁶, wherein R¹¹⁶ isalkyl of 1 to 3 carbon atoms, (i) —CN, (j) the halogen atoms, (k)heterocycles selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and (l) arylor heteroaryl selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl, (vii) —SO₂R¹⁰⁸,wherein R¹⁰⁸ is: (a) phenyl, wherein said phenyl moiety is optionallysubstituted with one or more moieties selected from the class consistingof the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and—OR¹¹⁷ (wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) aheterocyclic group selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein saidheterocyclic group is optionally substituted with one or more moietiesselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁸ (wherein R¹¹⁸ is hydrogenor alkyl of 1 to 6 carbon atoms), or (c) straight or branched alkyl of 1to 7 atoms, wherein said alkyl moiety is optionally substituted with oneor more moieties selected from the class consisting of the halogenatoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (whereinR¹¹⁹ is hydrogen or alkyl of 1 to 6 carbon atoms), (viii) —COR¹⁰⁹,wherein R¹⁰⁹ is: (a) phenyl, wherein said phenyl moiety is optionallysubstituted with one or more moieties selected from the class consistingof the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and—OR¹²⁰ (wherein R¹²⁰ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) aheterocyclic group selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein saidheterocyclyl is optionally substituted with one or more halogen,straight or branched alkyl of 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ ishydrogen or alkyl of 1 to 6 carbon atoms), or (c) straight or branchedalkyl of 1 to 7 atoms, wherein said alkyl moiety is optionallysubstituted with one or more moieties selected from the class consistingof the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and—OR¹²² (wherein R¹²² is hydrogen or alkyl of 1 to 6 carbon atoms), and(ix) —CHO; X is an oxygen atom; R³ is branched or unbranched alkyl of 1to 3 carbon atoms; R⁴ is a group of the formula —CH₂R⁵⁵, wherein, R⁵⁵is: phenyl, which is optionally substituted at the 4-position with: (A)R^(59e), which is aryl or heteroaryl selected from the class consistingof phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl, wherein one ofthe hydrogen atoms of said aryl or heteroaryl group is optionallyreplaced with: (i) methyl, (ii) —CN, (iii) nitro, or (iv) halogen, (B)methyl, (C) —CN, (D) nitro, or (E) halogen; R⁵ is Cl; Z is ═C(H)—; and,R⁷ is Cl; or a pharmaceutically acceptable salt thereof.
 7. A compoundof the formula I, as set forth in claim 1, wherein: A¹ is ═N—; A² is═C(H)—; D is ═C(SO₂R¹)— or ═C(C(O)R¹)—, wherein R¹ is selected from theclass consisting of: (A) —R^(100e), which is: branched or unbranchedalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, inwhich alkyl, or cycloalkyl group one to three hydrogen atoms areoptionally and independently replaced with: (i) oxo, (ii) a group of theformula —COOR¹⁸, wherein R¹⁸ is straight or branched alkyl of 1 to 7carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (iii) a group of theformula —CONR¹⁹R²⁰, wherein R¹⁹ and R²⁰ are each, independently, ahydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6carbon atoms, or wherein R¹⁹ and R²⁰ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, and wherein one carbon atom insaid hydrocarbon bridge is optionally replaced by —O—, —NH—, or —NMe-,(iv) a group of the formula —OR²¹, wherein R²¹ is a hydrogen atom, or astraight or branched alkyl or acyl group of 1 to 7 carbon atoms, or (v)a group of the formula —NR²³R²⁴, wherein R²³ and R²⁴ are each,independently, (a) a hydrogen atom, (b) straight or branched alkyl oracyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, (c) agroup of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or 2, (d) a groupof the formula —(CH₂)_(n)COOR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵is straight or branched alkyl of 1 to 6 carbon atoms, or (e) a group ofthe formula —(CH₂)_(n)CONHR²⁵, wherein n is 0, 1 or 2, and wherein R²⁵is straight or branched alkyl of 1 to 6 carbon atoms, and (B) saturatedheterocyclic groups selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein saidheterocyclic groups are optionally mono- or di-substituted with moietiesindependently selected from the class consisting of: (i) oxo, (ii)—OR¹⁰¹, wherein R¹⁰¹ is: (a) a hydrogen atom, (b) alkyl of 1 to 7carbons, wherein one hydrogen atom of said alkyl group is optionallyreplaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is an alkyl moiety of 1 to 6carbon atoms), —NH₂, —NHMe or —NMe₂, (c) acyl of 1 to 7 carbons, whereinone hydrogen atom of said acyl group is optionally replaced with —OH,—OR¹¹¹ (wherein R¹¹¹ is an alkyl moiety of 1 to 6 carbon atoms), —NH₂,—NHMe or —NMe₂, (d) —CONR¹⁰²R¹⁰³, wherein R¹⁰² and R¹⁰³ are eachindependently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R¹⁰²and R¹⁰³ constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, or (e) —COOR¹⁰⁴,wherein R¹⁰⁴ is alkyl of 1 to 7 atoms, (iii) —CONR¹⁰⁵R¹⁰⁶, wherein R¹⁰⁵and R¹⁰⁶ are each independently: (a) a hydrogen atom, or (b) straight orbranched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms, whereinsaid alkyl or cycloalkyl group is optionally monosubstituted with —OH,—OR¹²³ (wherein R¹²³ is an alkyl moiety of 1 to 6 carbon atoms), —NH₂,—NHMe, —NMe₂, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or,wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (iv) —COOR¹⁰⁷,wherein R¹⁰⁷ is a hydrogen atom, or straight or branched alkyl of 1 to 7carbon atoms, (v) straight or branched alkyl of 1 to 7 carbon atoms orcycloalkyl of 3 to 7 carbons, wherein one to three hydrogen atoms ofsaid alkyl or cycloalkyl group is optionally replaced with a moietyindependently selected from the class consisting of: (a) oxo, (b) —OH,(c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbon atoms, (d) —OCOCH₃,(e) —NH₂, (f) —NHMe, (g) —NMe₂, (h) —CO₂H, and (i) —CO₂ R¹¹⁴ whereinR¹¹⁴ is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched orcyclic, and wherein one or two hydrogen atoms of said acyl group isoptionally replaced with a moiety selected from the class consisting of:(a) —OH, (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6 carbon atoms, (c)—NH₂, (d) —NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo, (h) —CO₂ R¹¹⁶, whereinR¹¹⁶ is alkyl of 1 to 3 carbon atoms, (i) —CN, (j) the halogen atoms,(k) heterocycles selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and (l) arylor heteroaryl selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl, (vii) —SO₂R¹⁰⁸,wherein R¹⁰⁸ is: (a) phenyl, wherein said phenyl moiety is optionallysubstituted with one moiety selected from the class consisting of thehalogen atoms, straight or branched alkyl of 1 to 6 carbons, and —OR¹⁷(wherein R¹¹⁷ is hydrogen or alkyl of 1 to 6 carbon atoms), (b) aheterocyclic group selected from the class consisting of pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein saidheterocyclic group is optionally substituted with one moiety selectedfrom the class consisting of the halogen atoms, straight or branchedalkyl of 1 to 6 carbons, and —OR¹⁸ (wherein R¹¹⁸ is hydrogen or alkyl of1 to 6 carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms,wherein said alkyl moiety is optionally substituted with one moietyselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹¹⁹ (wherein R¹¹⁹ is hydrogenor alkyl of 1 to 6 carbon atoms), (viii) —COR¹⁰⁹, wherein R¹⁰⁹ is: (a)phenyl, wherein said phenyl moiety is optionally substituted with onemoiety selected from the class consisting of the halogen atoms, straightor branched alkyl of 1 to 6 carbons, and —OR¹²⁰ (wherein R¹²⁰ ishydrogen or alkyl of 1 to 6 carbon atoms), (b) a heterocyclic groupselected from the class consisting of pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclylis optionally substituted with one halogen, straight or branched alkylof 1 to 6 carbons, or —OR¹²¹ (wherein R¹²¹ is hydrogen or alkyl of 1 to6 carbon atoms), or (c) straight or branched alkyl of 1 to 7 atoms,wherein said alkyl moiety is optionally substituted with one moeityselected from the class consisting of the halogen atoms, straight orbranched alkyl of 1 to 6 carbons, and —OR¹²² (wherein R¹²² is hydrogenor alkyl of 1 to 6 carbon atoms), and (ix) —CHO; X is an oxygen atom; R³is branched or unbranched alkyl of 1 to 3 carbon atoms; R⁴ is a group ofthe formula —CH₂R⁵⁵, wherein, R⁵⁵ is: phenyl, which is optionallysubstituted at the 4-position with: (A) R^(59e), which is aryl orheteroaryl selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl and furyl, wherein one of the hydrogen atoms ofsaid aryl or heteroaryl group is optionally replaced with: (i) methyl,(ii) —CN, (iii) nitro, or (iv) halogen, (B) methyl, (C) —CN, (D) nitro,or (E) halogen; R⁵ is Cl; Z is ═C(H)—; and, R⁷ is Cl; or apharmaceutically acceptable salt thereof.
 8. A compound of the formulaI, as set forth in claim 1, wherein: A¹ is ═N—; A² is ═C(H)—; D is═C(SO₂R¹)—, wherein R¹ is selected from the class consisting of: (A)methyl, and (B) saturated heterocyclic groups selected from the classconsisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinylwherein said heterocyclic groups are optionally mono- or di-substitutedwith moieties independently selected from the class consisting of: (i)oxo, (ii) —OR¹⁰¹, wherein R¹⁰¹ is: (a) a hydrogen atom, (b) alkyl of 1to 7 carbons, wherein one hydrogen atom of said alkyl group isoptionally replaced with —OH, —OR¹¹⁰ (wherein R¹¹⁰ is an alkyl moiety of1 to 6 carbon atoms), —NH₂, —NHMe or —NMe₂, or (c) acyl of 1 to 7carbons, wherein one hydrogen atom of said acyl group is optionallyreplaced with —OH, —OR¹¹¹ (wherein R¹¹¹ is an alkyl moiety of 1 to 6carbon atoms), —NH₂, —NHMe or —NMe₂, (iii) —CONR¹⁰⁵R⁰⁶, wherein R¹⁰⁵ andR¹⁰⁶ are each independently: (a) a hydrogen atom, or (b) straight orbranched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms, whereinsaid alkyl or cycloalkyl group is optionally monosubstituted with —OH,—OR¹²³ (wherein R¹²³ is an alkyl moiety of 1 to 6 carbon atoms), —NH₂,—NHMe, —NMe₂, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or,wherein R¹⁰⁵ and R¹⁰⁶ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one carbon atom in said hydrocarbonbridge is optionally replaced by —O—, —NH—, or —NMe-, (iv) —COOR¹⁰⁷,wherein R¹⁰⁷ is a hydrogen atom, or straight or branched alkyl of 1 to 7carbon atoms, (v) straight or branched alkyl of 1 to 7 carbon atomswherein one or two hydrogen atoms of said alkyl group are optionallyreplaced with moieties independently selected from the class consistingof: (a) oxo, (b) —OH, (c) —OR¹¹³, wherein R¹¹³ is alkyl of 1 to 6 carbonatoms, (d) —OCOCH₃, (e) —NH₂, (f) —NHMe, (g) —NMe₂, (h) —CO₂H, and (i)—CO₂ R¹¹⁴ wherein R¹¹⁴ is alkyl of 1 to 3 carbon atoms, or cycloalkyl of3 to 7 carbons, (vi) acyl of 1 to 7 carbon atoms, which may be straight,branched or cyclic, and wherein one or two hydrogen atoms of said acylgroup is optionally replaced with a moiety selected from the classconsisting of: (a) —OH, (b) —OR¹¹⁵, wherein R¹¹⁵ is alkyl of 1 to 6carbon atoms, (c) —NH₂, (d) —NHMe, (e) —NMe₂, (f) —NHCOMe, (g) oxo, (h)—CO₂ R¹¹⁶, wherein R¹¹⁶ is alkyl of 1 to 3 carbon atoms, (i) —CN, (j)the halogen atoms, (k) heterocycles selected from the class consistingof pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl, and (l) aryl or heteroaryl selected from the classconsisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyland oxazolyl, (vii) —SO₂R¹⁰⁸, wherein R¹⁰⁸ is: (a) a heterocyclic groupselected from the class consisting of pyrrolidinyl, piperidinyl,piperazinyl and morpholinyl wherein said heterocyclic group isoptionally substituted with one moiety selected from the classconsisting of straight or branched alkyl of 1 to 6 carbons, and —OR¹¹⁸(wherein R¹¹⁸ is hydrogen or alkyl of 1 to 6 carbon atoms), (viii)—COR¹⁰⁹, wherein R¹⁰⁹ is: (a) a heterocyclic group selected from theclass consisting of pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl wherein said heterocyclyl is optionally substituted with onehalogen, straight or branched alkyl of 1 to 6 carbons, or —OR¹²¹(wherein R¹²¹ is hydrogen or alkyl of 1 to 6 carbon atoms), and (ix)—CHO; X is an oxygen atom; R³ is methyl; R⁴ is a group of the formula—CH₂R⁵⁵, wherein, R⁵⁵ is: phenyl, which is optionally substituted at the4-position with: (A) R^(59e), which is aryl or heteroaryl selected fromthe class consisting of phenyl, pyridyl, and pyrimidinyl (B) —CN, (B)nitro, or (C) halogen; R⁵ is Cl; Z is ═C(H)—; and, R⁷ is Cl; or apharmaceutically acceptable salt thereof.
 9. A compound of the formulaI, in accordance with claim 1, 2, 3, 4, 5, 6, 7 or 8, with the absolutestereochemistry depicted below in formula II (below).


10. A compound of the formula I, in accordance with claim 1, selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 11. A method for thetreatment or prophylaxis of inflammatory or immune cell-mediateddiseases which comprises administering to a host in need or suchtreatment or prophylaxis a therapeutic or prophylactic amount of acompound in accordance with claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or
 10. 12.The method of claim 11 wherein the disease or condition is selected fromthe group consisting of adult respiratory distress syndrome, shock,oxygen toxicity, multiple organ injury syndrome secondary to septicemia,multiple organ injury syndrome secondary to trauma, reperfusion injuryof tissue due to cardiopulmonary bypass, myocardial infarction or usewith thrombolysis agents, acute glomerulonephritis, vasculitis, reactivearthritis, dermatosis with acute inflammatory components, stroke,thermal injury, hemodialysis, leukapheresis, ulcerative colitis,necrotizing enterocolitis and granulocyte transfusion associatedsyndrome.
 13. The method of claim 11 wherein the disease or condition isselected from the group consisting of psoriasis, organ/tissue transplantrejection, graft vs. host reactions and autoimmune diseases includingRaynaud's syndrome, autoimmune thyroiditis, dermatitis, multiplesclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus,uveitis, inflammatory bowel disease including Crohn's disease andulcerative colitis; and systemic lupus erythematosus.
 14. The method ofclaim 11 wherein the disease or condition is asthma.
 15. The method ofclaim 11 wherein the condition is toxicity associated with cytokinetherapy.
 16. The method of claim 11 wherein the disease or condition ispsoriasis.
 17. A pharmaceutical composition comprising a compound inaccordance with claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or
 10. 18. A compound ofthe formula

wherein, R¹ is selected from the class consisting of: (A) hydrogen, (B)the halogen atoms, and (C) SO₂ ⁻M⁺, wherein M⁺ is (i) Li⁺, (ii) Na⁺,(iii) K⁺, or (iv) MgX+, wherein X is a halogen; and R² is selected fromthe class consisting of: (A) the halogen atoms, (B) aryl, selected fromthe class of (i) phenyl, (ii) pyridyl, and (iii) pyrimidyl, and (C) CN.19. In accordance with claim 18, the compound of the following formula:


20. In accordance with claim 18, the compound of the following formula:


21. In accordance with claim 18, the compound of the following formula: